{"gene":"BCAP31","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1997,"finding":"BAP31 (p28) is a polytopic integral ER membrane protein that forms a complex with Bcl-2/Bcl-XL and procaspase-8 (FLICE). Caspase-8 and caspase-1 (but not caspase-3) cleave BAP31 at two identical AAVD.G caspase recognition sites in vitro, generating a p20 fragment. Bax prevents Bcl-2 from associating with the complex. The p20 fragment induces apoptosis when expressed ectopically.","method":"Co-immunoprecipitation in co-transfected 293T cells; in vitro caspase cleavage assays; ectopic expression of p20 fragment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, in vitro enzymatic assay, mutagenesis, functional ectopic expression; foundational paper replicated by multiple subsequent studies","pmids":["9334338"],"is_preprint":false},{"year":1996,"finding":"BAP31 preferentially associates with membrane IgD but not IgM, and specific amino acids in the transmembrane sequence of the IgD heavy chain (delta-m chain) are critical for binding to BAP29/BAP31, as determined by mutational analysis.","method":"Mutagenesis of IgD transmembrane domain; co-immunoprecipitation; cloning and sequence analysis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutational analysis with Co-IP; single lab but two orthogonal methods","pmids":["8612576"],"is_preprint":false},{"year":1997,"finding":"BAP31 controls ER-to-Golgi anterograde transport of cellubrevin; BAP31 and cellubrevin interact via their transmembrane regions (sensitive to high ionic strength); truncation of the BAP31 cytoplasmic tail prevents ER export of cellubrevin but not of the transferrin receptor. BAP31 localizes to the ER and a paranuclear vesicular compartment dependent on intact microtubules.","method":"Co-immunoprecipitation from fibroblast detergent extracts; affinity pulldown with recombinant cellubrevin; immunocytochemistry; BAP31 cytoplasmic-tail truncation mutants; nocodazole treatment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, pulldown, dominant-negative truncation mutant with specific cargo readout; replicated conceptually across multiple subsequent studies","pmids":["9396746"],"is_preprint":false},{"year":1998,"finding":"The predicted death effector homology (vDED) domain in the cytosolic region of BAP31 interacts with CED-4, which in turn contributes to recruitment of procaspase-8 to the BAP31 complex. Bcl-XL binds directly but weakly to the transmembrane region of BAP31, and indirectly and cooperatively to the cytosolic domain dependent on procaspase-8 and CED-4. CED-4Δc displaces Bcl-XL from the complex.","method":"Co-immunoprecipitation in co-transfected human cells; domain-mapping experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, single lab, two orthogonal approaches","pmids":["9452422"],"is_preprint":false},{"year":2000,"finding":"Caspase-resistant BAP31 (crBAP31, with AAVD→AAVA mutations) blocks Fas-mediated cytochrome c release from mitochondria and membrane fragmentation, demonstrating that uncleaved full-length BAP31 is an inhibitor of these apoptotic events. The data reveal unexpected ER-mitochondria crosstalk during Fas apoptosis mediated through BAP31 cleavage status.","method":"Stable expression of caspase-resistant BAP31 mutant in KB epithelial cells; Fas stimulation; measurement of cytochrome c release, caspase activation, phosphatidylserine redistribution, mitochondrial membrane potential","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function (caspase-resistant mutant) with multiple orthogonal apoptotic readouts; foundational paper independently replicated","pmids":["10958671"],"is_preprint":false},{"year":2001,"finding":"BAP31 controls expression and ER-membrane retention of CFTR; antisense inhibition of BAP31 increases CFTR expression and enables cAMP-activated Cl⁻ currents in ΔF508-CFTR-expressing CHO cells; coexpression of CFTR with BAP31 attenuates cAMP-activated Cl⁻ currents in Xenopus oocytes. BAP31 and CFTR colocalize in the cytosol.","method":"Antisense knockdown of BAP31 in CHO cells; co-expression in Xenopus oocytes with electrophysiology; immunofluorescence colocalization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function knockdown plus electrophysiological functional readout; single lab, two orthogonal methods","pmids":["11274174"],"is_preprint":false},{"year":2002,"finding":"Procaspase-8L, characterized by an N-terminal extension (Nex) domain, is selectively recruited to the BAP31 complex at the ER via its Nex domain. Gene deletion of BAP31 and the related BAP29 impairs processing of procaspase-8L in response to E1A by a FADD-independent, BCL-2-inhibitable mechanism, and curtails downstream caspase activation and cell death.","method":"BAP31/BAP29 gene deletion in mouse cells; dominant-negative Nex-domain mutant; co-immunoprecipitation; caspase activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene deletion, dominant-negative, Co-IP, functional caspase assays in one study; clear epistatic placement","pmids":["11917123"],"is_preprint":false},{"year":2003,"finding":"The p20 caspase-8 cleavage fragment of BAP31 triggers Ca²⁺ release from the ER, concomitant Ca²⁺ uptake into mitochondria, and mitochondrial recruitment of Drp1, resulting in mitochondrial fission. Inhibition of Drp1 or ER-mitochondrial Ca²⁺ signaling prevents p20-induced fission. p20 sensitizes mitochondria to caspase-8-induced cytochrome c release.","method":"Adenoviral expression of p20 BAP31 fragment; Ca²⁺ imaging; mitochondrial morphology assays; Drp1 dominant-negative inhibition; cytochrome c release assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Ca²⁺ imaging, morphology, inhibition of Drp1, cytochrome c release) in single rigorous study; independently replicated concept","pmids":["12668660"],"is_preprint":false},{"year":2003,"finding":"Full-length BAP31, in association with the putative ER ion channel protein A4 (a constitutive BAP31-binding partner identified by split-ubiquitin yeast two-hybrid), is a direct inhibitor of BAX/BAK oligomerization and cytochrome c release downstream of caspase-8 activation, acting independently of its ability to generate p20.","method":"Split-ubiquitin yeast two-hybrid screen; co-immunoprecipitation; reconstitution in Bap31-null mouse cells; FKBPcasp8 inducible system; cytochrome c release assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid identification plus Co-IP confirmation, null-cell reconstitution, inducible caspase system; multiple methods in one study","pmids":["12529377"],"is_preprint":false},{"year":2003,"finding":"BAP31 specifically associates with nonmuscle myosin heavy chain B and nonmuscle gamma-actin (components of the actomyosin cytoskeleton), and Fas-induced apoptosis releases these associations, potentially contributing to membrane remodelling during apoptosis.","method":"Capillary LC-MS/MS characterization of BAP31 immunocomplex from HepG2 cells; co-immunoprecipitation","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — MS identification confirmed by Co-IP; single lab","pmids":["12605685"],"is_preprint":false},{"year":2003,"finding":"BAP29/BAP31 form high-molecular-weight complexes in the ER that retain membrane-bound IgD lacking its Ig-α/Ig-β subunits. In Drosophila S2 cells, surface appearance of IgD is prevented by coexpression of BAP29 and BAP31. The retention mechanism is true ER retention, not retrieval from a post-ER compartment.","method":"Blue native PAGE; co-immunoprecipitation; heterologous expression in Drosophila S2 cells; immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blue native PAGE, heterologous system, Co-IP; single lab with multiple orthogonal approaches","pmids":["12886015"],"is_preprint":false},{"year":2004,"finding":"BAP31 specifically binds to CD11b/CD18 (beta-2 integrin) via the cytoplasmic tail of BAP31; the interaction is not dependent on divalent cations or the CD11b I-domain. BAP31 and CD11b/CD18 colocalize in neutrophil secondary granules and both redistribute to the plasma membrane upon fMLP stimulation.","method":"Monoclonal antibody co-precipitation; co-immunoprecipitation; GST-fusion binding assays; immunolocalization; subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, GST pulldown, domain mapping, colocalization; single lab","pmids":["15294914"],"is_preprint":false},{"year":2004,"finding":"BAP31 is required for stability of a novel ER integral membrane protein PTPLB; in Bap31-null mouse cells PTPLB turns over more rapidly via proteasomal degradation, whereas reconstitution with human BAP31 maintains PTPLB levels, consistent with a chaperone/quality control function for BAP31 in the ER membrane.","method":"Split-ubiquitin cDNA library screen; Bap31-null mouse cells reconstituted with BAP31; proteasome inhibitor experiments; turnover assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null reconstitution plus split-ubiquitin identification; single lab, two orthogonal methods","pmids":["15024066"],"is_preprint":false},{"year":2005,"finding":"BAP31 is required for cell-surface expression of tetraspanins CD9 and CD81; in Bap31-null mouse cells, CD9 and CD81 surface levels are reduced, integrin-mediated cell adhesion to extracellular matrix is impaired under serum stress, and cells are sensitized to apoptosis. Reconstitution of BAP31 restores surface tetraspanin levels and integrin-mediated survival. The p20 BAP31 cleavage product inhibits egress of tetraspanins and integrin-mediated cell attachment.","method":"Bap31-null mouse cells; reconstitution with wild-type BAP31; p20 BAP31 ectopic expression; flow cytometry for surface tetraspanins; adhesion and apoptosis assays; antibody antagonism of CD9/integrins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — null cells, reconstitution, p20 expression, multiple orthogonal cellular assays in one study","pmids":["15946936"],"is_preprint":false},{"year":2005,"finding":"BAP31 interacts with cytochrome P450 2C2 in the ER via transmembrane domain interactions (shown by bimolecular fluorescence complementation and Co-IP); BAP31 depletion causes redistribution of P450 2C2 from the ER to nuclear membrane and cell surface, and increases P450 2C2 expression levels, indicating BAP31 retains P450 2C2 in the ER.","method":"Bimolecular fluorescence complementation (BiFC); co-immunoprecipitation; siRNA knockdown of BAP31; Bap31-null ES cells reconstituted with BAP31; immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BiFC plus Co-IP plus null-cell reconstitution; single lab","pmids":["16332681"],"is_preprint":false},{"year":2006,"finding":"BAP31 enhances ER export of peptide-loaded MHC class I molecules; overexpression of BAP31 increases surface class I levels by accelerating ER export and stabilizing exported molecules. BAP31 may also retrieve peptide-depleted class I from post-ER acidic compartments. Overexpression of the homolog BAP29 decreases surface class I levels.","method":"Transfection of YFP-Bap31 chimeras in HeLa cells; flow cytometry for surface MHC class I; pulse-chase experiments; comparison with BAP29 overexpression","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — overexpression with functional surface-level readout, pulse-chase kinetics; single lab","pmids":["17056546"],"is_preprint":false},{"year":2008,"finding":"BAP31 is an itinerant ER protein that cycles between the peripheral ER and a juxtanuclear ER-related quality control compartment; this cycling depends on microtubules and dynein-dynactin function. The third and second transmembrane domains of BAP31 are principally responsible for movement to and recycling from the juxtanuclear region, respectively. Sar1p and Arf1 mutants affect BAP31 cycling.","method":"Live-cell fluorescence imaging with GFP-Bap31; FRAP; dominant-negative Sar1p and Arf1 mutants; microtubule depolymerization (nocodazole); dynein-dynactin disruption; transmembrane domain deletion mutants","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging, FRAP, multiple dominant-negative mutants, transmembrane domain mapping; multiple orthogonal methods in one study","pmids":["18287538"],"is_preprint":false},{"year":2008,"finding":"BAP31 associates with two components of the Sec61 preprotein translocon (Sec61β and TRAM); BAP31 associates with the N-terminus of newly synthesized ΔF508-CFTR and promotes its retrotranslocation and degradation by the 26S proteasome. Depletion of BAP31 reduces proteasomal degradation of ΔF508 and allows it to reach the cell surface. BAP31 also physically and functionally associates with the Derlin-1 dislocation complex in the ΔF508 degradation pathway.","method":"Co-immunoprecipitation; siRNA depletion of BAP31; pulse-chase degradation assays; proteasome inhibition; cell-surface biotinylation; Derlin-1 association","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with multiple partners, siRNA KD, pulse-chase, cell-surface assay; multiple orthogonal methods; published in high-tier journal","pmids":["18555783"],"is_preprint":false},{"year":2008,"finding":"BAP31 interacts with HPV E5 proteins (HPV16 and HPV31); interaction confirmed by split-ubiquitin yeast two-hybrid and coimmunoprecipitation. Amino acids in the extreme C-terminus of E5 are required for stabilizing the interaction. Deletion of C-terminal E5 residues in complete HPV31 genomes impairs proliferative capacity of keratinocytes upon differentiation; siRNA knockdown of Bap31 similarly reduces this proliferative ability.","method":"Split-ubiquitin yeast two-hybrid screen; co-immunoprecipitation; E5 C-terminal deletion mutants in HPV31 genomes; siRNA knockdown of Bap31; colocalization (immunofluorescence)","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — split-ubiquitin plus Co-IP confirmation, mutational analysis, functional siRNA; single lab","pmids":["18684816"],"is_preprint":false},{"year":2009,"finding":"BAP31 clusters with MHC class I (HLA-A2) in the ER and traffics with it to the ERGIC via export vesicles; FRET between BAP31 and HLA-A2 and forward traffic increase when class I molecules are loaded with peptide. Overexpression of BAP29 blocks BAP31-mediated forward traffic of class I.","method":"FRET (Förster resonance energy transfer); quantitative fluorescence microscopy; peptide pulse experiments; BAP29 overexpression","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET and quantitative imaging with functional peptide-loading readout; single lab","pmids":["19342655"],"is_preprint":false},{"year":2010,"finding":"Fis1 (outer mitochondrial membrane fission protein) interacts with BAP31 at the ER membrane to form the 'ARCosome' platform spanning the mitochondria-ER interface. This complex facilitates cleavage of BAP31 into pro-apoptotic p20BAP31. The BAP31 vDED domain is required for recruitment of procaspase-8 to the Fis1-BAP31 complex, and this recruitment is required for procaspase-8 activation. Activation triggers ER Ca²⁺ release establishing a feedback loop to activate mitochondria.","method":"Co-immunoprecipitation; Fis1 and BAP31 overexpression/knockdown; procaspase-8 recruitment assays; Ca²⁺ release measurements; BAP31 vDED domain mutants","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, domain mutants, functional caspase activation, Ca²⁺ signaling; multiple orthogonal methods; independently replicated concept","pmids":["21183955"],"is_preprint":false},{"year":2010,"finding":"The yeast BAP31 homologs Yet1p and Yet3p form a complex (Yet complex) important for subunit stability and proper ER localization; the Yet complex is not efficiently packaged into COPII vesicles and is not an ER export receptor. Instead, a fraction of the Yet complex associates with the Sec61 ER translocation apparatus (Sec complex), and this association increases under ER stress and decreases when translocation substrates are depleted.","method":"Co-immunoprecipitation; COPII vesicle packaging assays; ER stress induction; genetic mutant analysis; protein stability assays in yeast","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast ortholog study; Co-IP, vesicle packaging assay, genetic epistasis; single lab","pmids":["20378542"],"is_preprint":false},{"year":2011,"finding":"BAP31 and the ER lumenal chaperone BiP are both required for dislocation of SV40 from the ER to the cytosol; both proteins colocalize with the virus in discrete foci. siRNA knockdown of BAP31 or BiP prevents ER-to-cytosol dislocation of SV40 particles. The ERAD machinery assists virus transport across the ER membrane.","method":"siRNA screen; immunofluorescence colocalization; SV40 infection and dislocation assays; siRNA knockdown functional validation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA screen with functional validation of dislocation assay; colocalization; published in high-tier journal with clear mechanistic readout","pmids":["21947079"],"is_preprint":false},{"year":2013,"finding":"CDIP1 (a proapoptotic p53 target) interacts with BAP31 at the ER membrane; upon ER stress CDIP1 is induced and enhances its association with BAP31. CDIP1 binding to BAP31 is required for BAP31 cleavage during ER stress and for BAP31-Bcl-2 association. The CDIP1-BAP31 complex recruits Bcl-2, promotes tBid and caspase-8 activation, and BAX oligomerization. CDIP1 knockout in mice impairs ER-stress-mediated apoptosis.","method":"Co-immunoprecipitation; ER stress induction; CDIP1 knockout mice; BAP31 cleavage assays; caspase-8 activation assays; BAX oligomerization","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, genetic KO mice, multiple functional apoptotic readouts; multiple orthogonal methods","pmids":["24139803"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function mutations in BCAP31 in humans result in ER morphology alteration and Golgi disorganization in primary fibroblasts, demonstrating that BAP31 is required for ER-to-Golgi crosstalk. Constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors (in contrast to transient RNAi experiments).","method":"Patient-derived primary fibroblasts with loss-of-function BCAP31 mutations; immunofluorescence for ER/Golgi morphology; UPR marker assays; Western blot for cell-death effectors","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient cell loss-of-function, multiple morphological and biochemical readouts; single study but human genetics validation","pmids":["24011989"],"is_preprint":false},{"year":2013,"finding":"The cytoplasmic variant of death effector domain (vDED) of BAP31 forms a dimeric parallel coiled coil (crystal structure determined), with no structural similarity to canonical DED domains. Solution studies confirm this coiled-coil conformation and suggest an additional C-terminal alpha-helical coiled-coil domain. BAP29 vDED is partially unfolded at neutral pH in vitro.","method":"X-ray crystallography (two crystal forms); circular dichroism; size-exclusion chromatography; solution biophysical characterization","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure solved plus orthogonal solution biophysical validation; single lab but direct structural determination","pmids":["23967155"],"is_preprint":false},{"year":2015,"finding":"BAP31 directly interacts with the RSV small hydrophobic (SH) protein; the C-terminal endodomain of BAP31 and SH protein interact directly as shown by NMR titration of purified proteins in detergent micelles, and SH protein pulls down endogenous BAP31.","method":"Membrane-based yeast two-hybrid; co-immunoprecipitation (pull-down); NMR titration of purified proteins","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro NMR direct binding assay plus pull-down; single lab","pmids":["25854864"],"is_preprint":false},{"year":2015,"finding":"BAP31 on the cell surface of human embryonic stem cells exposes its C-terminal domain extracellularly, representing a novel membrane topology distinct from its canonical ER orientation (where C-terminus faces cytosol). Epitope mapping with deletion mutants confirmed that both cytoplasm-facing and surface-exposed C-terminal residues 208–217 are recognized by antibodies.","method":"Monoclonal antibody epitope mapping; GST-fused BAP31 serial C-terminal deletion mutants; immunofluorescence on hESCs and mESCs","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epitope mapping via antibodies and deletion constructs; single lab, no functional consequence established","pmids":["26102500"],"is_preprint":false},{"year":2017,"finding":"BAP31 is required for T cell activation through TCR signaling; BAP31 conditional knockdown in mouse thymus reduces T cell numbers and proliferation, decreases phosphorylation of ZAP70, Lck, Lat (upstream TCR), and Akt, GSK, JNK, ERK (downstream), and reduces TCRα/β/CD3 expression and cytokines (IL-2, IFN-γ, IL-6, TNF-α).","method":"Conditional BAP31 knockdown mouse (Cre/loxP); T cell proliferation assays; Western blot for phosphorylated TCR signaling components; flow cytometry for surface markers; ELISA for cytokines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse model with multiple TCR pathway phosphorylation readouts; single lab","pmids":["28333124"],"is_preprint":false},{"year":2018,"finding":"BAP31 is a binding partner of RTN3 and positively regulates RTN3 monomer stability; BAP31 knockout in hippocampal neurons increases RTN3 aggregate formation and decreases RTN3 monomer availability, enhancing BACE1-mediated APP processing and amyloid-β plaque deposition in an Alzheimer's disease mouse model.","method":"Co-immunoprecipitation; conditional BAP31 KO mice crossed with APP/PS1 AD model mice; Western blot for RTN3 monomer vs. aggregates; BACE1 activity; amyloid plaque quantification","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus conditional KO in disease model; multiple readouts; single lab","pmids":["30596517"],"is_preprint":false},{"year":2017,"finding":"Hepatocyte-specific deletion of BAP31 increases SREBP1C expression and activity; immunoprecipitation shows BAP31 interacts with SREBP1C and INSIG1; BAP31 deletion reduces INSIG1 expression, suggesting BAP31 regulates SREBP1C activity by modulating INSIG1 levels, leading to increased hepatic lipid accumulation and ER stress.","method":"Hepatocyte-specific conditional BAP31 KO mice; high-fat diet challenge; co-immunoprecipitation; Western blot for SREBP1C targets; hepatic lipid assays; ER stress markers","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mice plus Co-IP; multiple metabolic and signaling readouts; single lab","pmids":["29113994"],"is_preprint":false},{"year":2019,"finding":"BAP31 interacts with the mitochondrial import protein Tom40 within ER-mitochondria contact sites; the BAP31-Tom40 complex facilitates translocation of NDUFS4 (a complex I subunit) from the cytosol to mitochondria. Disruption of the BAP31-Tom40 complex inhibits mitochondrial complex I activity and oxygen consumption.","method":"Co-immunoprecipitation; NDUFS4 translocation assays; mitochondrial complex I activity assays; oxygen consumption measurements; BAP31 knockdown","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, protein translocation assay, mitochondrial functional assays; multiple orthogonal methods in a single rigorous study","pmids":["31206022"],"is_preprint":false},{"year":2019,"finding":"BAP31 inhibits autophagy by forming a BAP31-STX17 protein complex; loss of BAP31 stimulates tumor growth under metabolic stress conditions in vivo and enhances invasion activity. BAP31 acts to suppress ER stress adaptation and suppress autophagy.","method":"Co-immunoprecipitation of BAP31-STX17 complex; BAP31 KO cells; autophagy assays; xenograft tumor models; invasion assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus in vivo tumor model with functional readouts; single lab","pmids":["31671609"],"is_preprint":false},{"year":2019,"finding":"BCAP31 interacts with EGFR and acts as an inhibitor of ligand-independent EGFR recycling, sustaining EGFR autophosphorylation and activation of downstream signaling. BCAP31 knockdown reduces TNBC tumor growth.","method":"Co-immunoprecipitation; EGFR recycling/trafficking assays; phosphorylation assays; BCAP31 knockdown in vitro and in vivo","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus EGFR trafficking functional assay; single lab","pmids":["31588230"],"is_preprint":false},{"year":2019,"finding":"BAP31 specifically interacts with and regulates the proteasomal degradation of p27kip1 (cyclin kinase inhibitor); an intrabody (VH-D1) against BAP31 inhibits p27kip1 proteasome degradation, possibly by blocking BAP31-p27kip1 interaction, leading to suppressed proliferation and increased apoptosis in gastric cancer cells.","method":"Co-immunoprecipitation; intrabody expression; proteasome inhibitor assays; cell proliferation and apoptosis assays; xenograft mouse model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus functional intrabody blockade; single lab","pmids":["30338855"],"is_preprint":false},{"year":2019,"finding":"BAP31 deficiency in microglia upregulates IRAK1 protein levels, which in turn increases NF-κB p65 and c-Jun nuclear translocation and transcriptional activity, enhancing LPS-induced proinflammatory cytokine production. Knockdown of IRAK1 or an IRAK1 inhibitor reverses these effects.","method":"BAP31 conditional knockdown mice; BV2 cell knockdown; Western blot for IRAK1, phospho-NF-κB, phospho-c-Jun; ELISA for cytokines; immunofluorescence for NF-κB translocation; LPS-induced cognitive impairment model","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mice plus cellular knockdown, epistasis via IRAK1 inhibition; single lab","pmids":["31883536"],"is_preprint":false},{"year":2020,"finding":"BAP31 directly binds to SERPINE2 (serpin family E member 2); co-immunoprecipitation and immunofluorescence assays confirm the interaction; BAP31 promotes HCC tumor cell proliferation by stabilizing SERPINE2 and activating downstream Erk1/2 and p38 phosphorylation.","method":"Co-immunoprecipitation; immunofluorescence; RNA-seq; BAP31 knockdown/overexpression; tumor xenografts","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus RNA-seq with functional validation; single lab","pmids":["33363167"],"is_preprint":false},{"year":2023,"finding":"BAP31 interacts with VDAC1 at the ER-mitochondria interface and affects VDAC1 oligomerization and polyubiquitination; knockdown of BAP31 increases lipid peroxidation and promotes ferroptosis and G1/S arrest in gastric cancer. HNF4A binds the BAP31 promoter and increases its transcription.","method":"Co-immunoprecipitation; VDAC1 oligomerization assays; ubiquitination assays; ChIP for HNF4A at BAP31 promoter; BAP31 knockdown; ferroptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, oligomerization assay, ChIP; single lab with multiple methods","pmids":["37296105"],"is_preprint":false},{"year":2023,"finding":"BAP31 interacts with Perilipin1 via its C-terminal cytoplasmic domain on the surface of lipid droplets; BAP31 depletion represses Perilipin1 proteasomal degradation, leading to enhanced Perilipin1 expression, blocked lipid droplet degradation, supersized lipid droplet formation, impaired lipolysis, and altered adipogenesis.","method":"Co-immunoprecipitation; BAP31-adipocyte-specific KO mice; adipocyte differentiation of MEFs; lipolysis assays; proteasome inhibitor experiments; lipid droplet imaging","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mice, Co-IP domain mapping, functional lipolysis and adipogenesis assays; single lab","pmids":["37063427"],"is_preprint":false},{"year":2025,"finding":"Sirtuin 2 deacetylates BAP31 specifically at lysine 158 (K158); this deacetylation stabilizes BAP31 expression. Loss of sirtuin 2 reduces BAP31 expression. Carnosol upregulates sirtuin 2, which in turn deacetylates BAP31 to attenuate ER stress and hepatocyte apoptosis in alcoholic liver disease.","method":"Sirtuin 2 knockdown; site-specific acetylation mapping at K158; Western blot; alcohol-induced liver injury mouse model","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific PTM identification plus in vivo loss-of-function; single lab","pmids":["39887347"],"is_preprint":false},{"year":2025,"finding":"Crystal structure of the Fis1 cytosolic domain bound to the C-terminal vDED region of BAP31 reveals that the Bap31_vDED region engages the convex surface of Fis1's tetratricopeptide repeat (TPR) domain. One Fis1 structure features an N-terminal 'Fis1 arm' conformation suggestive of an autoinhibitory function.","method":"X-ray crystallography of Fis1 alone (two conformations) and Fis1-Bap31_vDED co-complex","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of co-complex directly defining the Fis1-Bap31 interaction surface; single study but direct structural determination","pmids":["40770055"],"is_preprint":false},{"year":2025,"finding":"PINK1 interacts with BAP31 and phosphorylates it at serine 142 (Ser142). PINK1-mediated phosphorylation of BAP31 is required for its neuroprotective effects against ER stress-mediated apoptosis; phosphomimetic BAP31-S142E strengthens protection while phospho-dead BAP31-S142A abolishes it.","method":"Co-immunoprecipitation; site-directed mutagenesis (S142A, S142E phosphomimetics); ER stress assays; PINK1 overexpression/knockdown; in vitro and in vivo neuronal models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phospho-site mutagenesis with functional apoptosis readout; single lab","pmids":["41022756"],"is_preprint":false},{"year":2024,"finding":"BCAP31 directly interacts with PINK1 and promotes PINK1 phosphorylation; BAP31 depletion reduces phosphorylated PINK1 levels, thereby inhibiting PINK1/Parkin-mediated mitophagy, leading to increased mitochondrial ROS, NF-κB activation, and alveolar epithelial cell apoptosis in acute lung injury.","method":"Co-immunoprecipitation (BAP31-PINK1); BCAP31 transgenic and conditional KO mice; mitophagy assays; mitochondrial ROS measurement; LPS-induced ALI model","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, transgenic and KO mice, mitophagy functional assays; single lab","pmids":["39381793"],"is_preprint":false},{"year":2024,"finding":"BAP31 is exploited by Legionella pneumophila; a Legionella effector Lpg1152 binds to BAP31. BAP31 together with Rab10 and Rab4 GTPases facilitates transitioning the Legionella-containing vacuole (LCV) from smooth ER to rough ER association. Optimal Legionella growth requires both BAP31 and Lpg1152.","method":"Co-immunoprecipitation of Lpg1152 with BAP31; BAP31 knockdown; Rab10/Rab4 knockdown; LCV morphology imaging; bacterial growth assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, siRNA KD with functional LCV and bacterial growth readouts; single lab","pmids":["39661521"],"is_preprint":false},{"year":2022,"finding":"BAP31 regulates ICAM-1 and VCAM-1 expression in endothelial cells via the MyD88/TRAF6-TAK1/NF-κB and PI3K/Akt signaling cascades; BAP31 knockdown deactivates these cascades, reducing NF-κB nuclear translocation and reducing neutrophil-endothelial cell adhesion in ALI.","method":"shBAP31 endothelial cell lines; endothelial-specific conditional BAP31 KO mice; luciferase reporter assays for ICAM-1/VCAM-1 promoters; ChIP; intravital microscopy; Western blot for NF-κB pathway proteins","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mice, ChIP, luciferase reporter, multiple signaling pathway readouts; single lab","pmids":["36549351"],"is_preprint":false},{"year":2023,"finding":"BAP31 promotes N-glycosylation of EpCAM by affecting the Sec61 translocation channel; the amino acid region 165-205 of BAP31 is important for this function. An intrabody (VH-F12) against this region inhibits EpCAM glycosylation.","method":"EpCAM glycosylation mutants (N76/111/198A); BAP31 C-terminal deletion constructs; intrabody expression; Western blot; Co-immunoprecipitation with Sec61","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — glycosylation mutants, BAP31 domain mapping, intrabody functional blockade; single lab","pmids":["37834237"],"is_preprint":false},{"year":2025,"finding":"BAP31 interacts with ELAVL1 (an RNA-binding protein) and promotes its maturation; ELAVL1 binds to the 3'UTR of SPINK6 mRNA to stabilize its expression. BAP31 silencing inhibits HCC cell invasion/migration and recovers cell polarity via reduction of SPINK6.","method":"IP-MS (immunoprecipitation mass spectrometry); immunofluorescence; RNA immunoprecipitation (RIP); RNA-FISH; RNA stability assays; luciferase reporter assay; in vivo metastasis model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus RIP plus RNA stability with functional metastasis readout; single lab, multiple orthogonal methods","pmids":["39990675"],"is_preprint":false},{"year":2025,"finding":"BAP31 interacts with PCMT1, a direct negative regulator of MST1 kinase; BAP31 knockdown activates MST1 and inhibits YAP transcription factor, suppressing breast cancer stemness via the Hippo pathway.","method":"Co-immunoprecipitation (BAP31-PCMT1); BAP31 knockdown; MST1 activity and YAP phosphorylation assays; tumor sphere formation; xenograft models","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with functional pathway readout; single lab, limited mechanistic depth","pmids":["40332113"],"is_preprint":false}],"current_model":"BAP31 is a polytopic ER integral membrane protein that functions as a broad-specificity chaperone/cargo receptor (controlling ER retention, export, retrotranslocation and ERAD of client transmembrane proteins including CFTR, MHC class I, CD9/CD81, cellubrevin, EGFR, SERPINE2, and others), a scaffold for apoptosis regulation at ER-mitochondria contact sites (forming complexes with Bcl-2/Bcl-XL, procaspase-8L, Fis1, and CDIP1; being cleaved by caspase-8 into pro-apoptotic p20 that triggers ER Ca²⁺ release, Drp1-dependent mitochondrial fission, and cytochrome c release), and a MAM tether that bridges mitochondria and ER via Tom40 to support mitochondrial complex I assembly, with its function further regulated by PINK1-mediated phosphorylation at Ser142 and sirtuin 2-mediated deacetylation at Lys158."},"narrative":{"mechanistic_narrative":"BCAP31 (BAP31) is a polytopic ER integral membrane protein that functions as a broad-specificity chaperone and quality-control factor governing ER retention, export, and ERAD of client transmembrane proteins, and as a scaffold that couples the ER to mitochondria for both apoptotic and metabolic signaling [PMID:9334338, PMID:9396746, PMID:18555783]. As a cargo/retention factor it controls ER-to-Golgi anterograde transport (cellubrevin export depends on its cytoplasmic tail) [PMID:9396746], retains immature or unassembled clients in the ER (membrane IgD, cytochrome P450 2C2) [PMID:12886015, PMID:16332681], promotes export and stabilization of peptide-loaded MHC class I [PMID:17056546, PMID:19342655], and supports surface delivery of tetraspanins CD9/CD81 to sustain integrin-mediated adhesion and survival [PMID:15946936]; it itinerates between peripheral ER and a juxtanuclear quality-control compartment in a microtubule- and dynein-dynactin-dependent manner [PMID:18287538]. Through association with the Sec61 translocon components Sec61β/TRAM and the Derlin-1 dislocation complex, BAP31 directs retrotranslocation and proteasomal degradation of misfolded clients such as ΔF508-CFTR [PMID:18555783]. BAP31 is also a central apoptosis regulator: full-length BAP31 forms a complex with Bcl-2/Bcl-XL and procaspase-8(L) and inhibits BAX/BAK oligomerization and cytochrome c release, while caspase-8/caspase-1 cleavage generates a pro-apoptotic p20 fragment that triggers ER Ca²⁺ release, Drp1-dependent mitochondrial fission, and sensitization to cytochrome c release [PMID:9334338, PMID:10958671, PMID:11917123, PMID:12668660, PMID:12529377]. This apoptotic platform is assembled at ER-mitochondria contacts with Fis1 (the 'ARCosome') and is engaged during ER stress through CDIP1 [PMID:21183955, PMID:24139803], with the BAP31 vDED region — structurally a coiled coil — directly binding the TPR domain of Fis1 [PMID:23967155, PMID:40770055]. At ER-mitochondria contacts BAP31 additionally tethers the mitochondrial import receptor Tom40 to deliver the complex I subunit NDUFS4 and support oxidative phosphorylation [PMID:31206022]. Loss-of-function mutations in BCAP31 in humans disrupt ER and Golgi morphology, establishing its requirement for ER-to-Golgi homeostasis [PMID:24011989]. Its activity is modulated by post-translational modification, including PINK1-mediated phosphorylation at Ser142 and sirtuin 2-mediated deacetylation at Lys158 [PMID:41022756, PMID:39887347].","teleology":[{"year":1997,"claim":"Established BAP31 as an ER membrane scaffold linking Bcl-2 family survival proteins to caspase-8, defining a caspase-cleavable substrate whose p20 product is itself pro-apoptotic.","evidence":"Reciprocal Co-IP in 293T cells, in vitro caspase cleavage with mutagenesis of AAVD sites, and ectopic p20 expression","pmids":["9334338"],"confidence":"High","gaps":["Did not establish the physiological trigger for cleavage in intact cells","Did not localize the activity to ER-mitochondria contacts"]},{"year":1996,"claim":"Identified BAP31/BAP29 as transmembrane-domain-selective binding partners of membrane immunoglobulin, first hinting at a cargo/retention role for ER-resident clients.","evidence":"Mutagenesis of the IgD delta-m transmembrane domain with Co-IP","pmids":["8612576"],"confidence":"Medium","gaps":["Functional consequence (retention vs export) of the IgD interaction not yet defined","Generality beyond IgD untested"]},{"year":1997,"claim":"Demonstrated that BAP31 actively controls ER export of a specific cargo, distinguishing a chaperone/export-receptor function from generic ER residence.","evidence":"Co-IP and recombinant pulldown with cellubrevin plus cytoplasmic-tail truncation mutants and nocodazole treatment in fibroblasts","pmids":["9396746"],"confidence":"High","gaps":["Did not define the COPII/export machinery BAP31 engages","Cargo selectivity rules not established"]},{"year":2000,"claim":"Showed that cleavage status converts BAP31 from a survival factor to a death signal, revealing ER-mitochondria crosstalk in Fas apoptosis.","evidence":"Stable caspase-resistant crBAP31 mutant in KB cells with cytochrome c release and mitochondrial readouts","pmids":["10958671"],"confidence":"High","gaps":["Molecular relay from ER cleavage to mitochondria not yet identified","Identity of mitochondrial effectors unknown at this stage"]},{"year":2002,"claim":"Placed BAP31/BAP29 epistatically upstream of procaspase-8L processing via a FADD-independent, Bcl-2-inhibitable route, defining a death-receptor-independent caspase-8 activation platform.","evidence":"BAP31/BAP29 gene deletion in mouse cells, dominant-negative Nex domain, Co-IP and caspase assays","pmids":["11917123"],"confidence":"High","gaps":["Spatial assembly of the platform not yet resolved","Stimulus specificity beyond E1A not fully mapped"]},{"year":2003,"claim":"Resolved how p20 reaches mitochondria, showing it drives ER Ca²⁺ release and Drp1-dependent fission that sensitizes mitochondria to cytochrome c release.","evidence":"Adenoviral p20 expression with Ca²⁺ imaging, mitochondrial morphology, Drp1 dominant-negative and cytochrome c assays","pmids":["12668660"],"confidence":"High","gaps":["Direct molecular target of p20 at the ER/mitochondria not defined","How Ca²⁺ release is gated by p20 unresolved"]},{"year":2003,"claim":"Defined the anti-apoptotic arm of full-length BAP31 as direct inhibition of BAX/BAK oligomerization, in partnership with the A4 ER channel protein and independent of p20 generation.","evidence":"Split-ubiquitin Y2H, Co-IP, Bap31-null reconstitution and inducible FKBPcasp8 cytochrome c assays","pmids":["12529377"],"confidence":"High","gaps":["Mechanism by which BAP31 restrains BAX/BAK not structurally defined","Role of A4 channel activity unresolved"]},{"year":1997,"claim":"Extended BAP31 quality control to disease-relevant transmembrane clients, showing it retains and limits surface delivery of CFTR.","evidence":"Antisense knockdown in CHO cells, Xenopus oocyte co-expression electrophysiology and colocalization (combined 2001 finding)","pmids":["11274174"],"confidence":"Medium","gaps":["Did not distinguish retention from degradation at this stage","ERAD machinery not yet linked"]},{"year":2004,"claim":"Broadened BAP31's role to active ER membrane protein quality control by showing it stabilizes a client (PTPLB) against proteasomal turnover.","evidence":"Split-ubiquitin cDNA screen, Bap31-null reconstitution and proteasome-inhibitor turnover assays","pmids":["15024066"],"confidence":"Medium","gaps":["Whether stabilization reflects folding assistance or degradation shielding unclear","Recognition determinants on clients unknown"]},{"year":2005,"claim":"Connected BAP31 quality control to cell physiology by linking tetraspanin surface delivery to integrin-mediated adhesion and apoptotic sensitivity.","evidence":"Bap31-null cells, reconstitution, p20 expression, flow cytometry and adhesion/apoptosis assays","pmids":["15946936"],"confidence":"High","gaps":["Direct binding to CD9/CD81 versus indirect chaperoning not fully resolved","Mechanism of p20 inhibition of egress unclear"]},{"year":2006,"claim":"Showed BAP31 promotes ER export and stabilization of peptide-loaded MHC class I, with the paralog BAP29 acting oppositely, refining its export-receptor function.","evidence":"YFP-Bap31 chimeras, surface class I flow cytometry and pulse-chase in HeLa cells (with 2009 FRET follow-up)","pmids":["17056546","19342655"],"confidence":"Medium","gaps":["Structural basis of peptide-loading-dependent recognition undefined","Quantitative contribution to antigen presentation in vivo not established"]},{"year":2008,"claim":"Mechanistically integrated BAP31 into ERAD by showing it associates with Sec61β/TRAM and the Derlin-1 complex to drive retrotranslocation and degradation of ΔF508-CFTR.","evidence":"Co-IP with translocon/dislocation components, siRNA depletion, pulse-chase and surface biotinylation","pmids":["18555783"],"confidence":"High","gaps":["How BAP31 selects clients for export versus dislocation not resolved","Stoichiometry within the dislocation complex unknown"]},{"year":2008,"claim":"Defined the itinerant cycling behavior and transmembrane-domain determinants underlying BAP31 trafficking between peripheral and juxtanuclear ER compartments.","evidence":"Live GFP-Bap31 imaging, FRAP, dominant-negative Sar1p/Arf1, nocodazole, dynein-dynactin disruption and TMD deletions","pmids":["18287538"],"confidence":"High","gaps":["Functional role of juxtanuclear cycling in quality control not established","Cargo coupling to the cycling pathway unresolved"]},{"year":2010,"claim":"Localized the apoptotic platform to ER-mitochondria contacts by identifying the Fis1-BAP31 'ARCosome' that recruits and activates procaspase-8 via the vDED domain.","evidence":"Co-IP, Fis1/BAP31 overexpression and knockdown, vDED mutants and Ca²⁺ release measurements","pmids":["21183955"],"confidence":"High","gaps":["Trigger that nucleates ARCosome assembly not defined","Quantitative Ca²⁺ feedback parameters unresolved"]},{"year":2013,"claim":"Linked ER stress to the BAP31 death platform by showing the p53 target CDIP1 binds BAP31, enables its cleavage, and recruits Bcl-2 to drive apoptosis.","evidence":"Co-IP, ER stress induction, CDIP1 knockout mice, BAP31 cleavage, caspase-8 and BAX oligomerization assays","pmids":["24139803"],"confidence":"High","gaps":["How CDIP1 binding licenses cleavage mechanistically unclear","Interplay with the Fis1 ARCosome not integrated"]},{"year":2013,"claim":"Provided structural insight that the BAP31 vDED is not a canonical DED but a parallel coiled coil, reframing how it scaffolds caspase recruitment.","evidence":"X-ray crystallography of the vDED with CD and SEC solution validation","pmids":["23967155"],"confidence":"High","gaps":["Structure of the full caspase-8/CED-4-bound complex unsolved","Functional coupling of the coiled coil to caspase activation untested structurally"]},{"year":2013,"claim":"Linked human BCAP31 loss-of-function to organelle morphology, establishing an in vivo requirement for ER-to-Golgi homeostasis distinct from the apoptotic/UPR axis.","evidence":"Patient-derived fibroblasts with LoF mutations, ER/Golgi immunofluorescence and UPR/cell-death marker assays","pmids":["24011989"],"confidence":"Medium","gaps":["Molecular basis of Golgi disorganization undefined","Which cargo defects drive the morphological phenotype unknown"]},{"year":2019,"claim":"Established a non-apoptotic metabolic role for BAP31 as an ER-mitochondria tether that delivers NDUFS4 to mitochondria via Tom40 to support complex I activity.","evidence":"Co-IP, NDUFS4 translocation, complex I activity and oxygen consumption assays with BAP31 knockdown","pmids":["31206022"],"confidence":"High","gaps":["How the same contact site partitions apoptotic versus import functions unclear","Generality to other imported subunits untested"]},{"year":2025,"claim":"Defined the atomic interface of the apoptotic tether, showing the BAP31 vDED engages the convex TPR surface of Fis1 with evidence for a Fis1 autoinhibitory arm.","evidence":"X-ray crystallography of Fis1 alone and the Fis1-Bap31_vDED co-complex","pmids":["40770055"],"confidence":"High","gaps":["How procaspase-8 docks onto this interface not resolved","Regulation of the proposed autoinhibitory arm in cells untested"]},{"year":2025,"claim":"Identified post-translational control of BAP31 stability and activity through PINK1 phosphorylation at Ser142 and sirtuin 2 deacetylation at Lys158.","evidence":"Co-IP, site-directed S142A/S142E mutagenesis with ER-stress apoptosis readouts; SIRT2 knockdown and K158 acetylation mapping in liver injury models","pmids":["41022756","39887347"],"confidence":"Medium","gaps":["How these modifications alter BAP31 conformation or partner binding mechanistically unclear","Crosstalk between phosphorylation and acetylation untested"]},{"year":null,"claim":"How BAP31 mechanistically partitions its many client and signaling roles — chaperone/export versus ERAD versus apoptotic scaffold versus mitochondrial tether — at a single ER-mitochondria platform remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of client recognition","Rules determining export versus dislocation versus retention undefined","Spatial/temporal switch between survival and death functions not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,15,13]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[12,14,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,20,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,16,24]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[20,31]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[38]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,16]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,4,7,20,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[17,12,15]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,13,16]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,17]}],"complexes":["ARCosome (Fis1-BAP31-procaspase-8 platform)","BAP31-Bcl-2/Bcl-XL-procaspase-8 complex","Derlin-1 dislocation complex","BAP31-Tom40 ER-mitochondria tether"],"partners":["BCL2L1","CASP8","FIS1","CDIP1","TOMM40","SEC61B","STX17","PINK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51572","full_name":"B-cell receptor-associated protein 31","aliases":["6C6-AG tumor-associated antigen","Protein CDM","p28"],"length_aa":246,"mass_kda":28.0,"function":"Functions as a chaperone protein (PubMed:18287538, PubMed:9396746). Is one of the most abundant endoplasmic reticulum (ER) proteins (PubMed:18287538, PubMed:9396746). Plays a role in the export of secreted proteins in the ER, the recognition of abnormally folded protein and their targeting to the ER associated-degradation (ERAD) (PubMed:18287538, PubMed:9396746). Also serves as a cargo receptor for the export of transmembrane proteins (By similarity). Plays a role in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) by stimulating the translocation of NDUFS4 and NDUFB11 from the cytosol to the mitochondria via interaction with TOMM40 (PubMed:31206022). In response to ER stress, delocalizes from the ER-mitochondria contact sites and binds BCL2 (PubMed:31206022). May be involved in CASP8-mediated apoptosis (PubMed:10958671)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P51572/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BCAP31","classification":"Not Classified","n_dependent_lines":177,"n_total_lines":1208,"dependency_fraction":0.14652317880794702},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000185825","cell_line_id":"CID000368","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"COPA","stoichiometry":4.0},{"gene":"COPB2","stoichiometry":4.0},{"gene":"COPE","stoichiometry":4.0},{"gene":"ARF4","stoichiometry":0.2},{"gene":"ARHGAP15","stoichiometry":0.2},{"gene":"ARL6IP1","stoichiometry":0.2},{"gene":"BCAP29","stoichiometry":0.2},{"gene":"TMX3","stoichiometry":0.2},{"gene":"ESYT1","stoichiometry":0.2},{"gene":"ATL3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000368","total_profiled":1310},"omim":[{"mim_id":"621108","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 18; DNAJC2","url":"https://www.omim.org/entry/621108"},{"mim_id":"619516","title":"BIFUNCTIONAL APOPTOSIS REGULATOR; BFAR","url":"https://www.omim.org/entry/619516"},{"mim_id":"615939","title":"PROTEIN TYROSINE PHOSPHATASE-LIKE (PROLINE INSTEAD OF CATALYTIC ARGININE), MEMBER B; PTPLB","url":"https://www.omim.org/entry/615939"},{"mim_id":"610423","title":"PHOSPHOFURIN ACIDIC CLUSTER SORTING PROTEIN 2; PACS2","url":"https://www.omim.org/entry/610423"},{"mim_id":"300475","title":"DEAFNESS, DYSTONIA, AND CEREBRAL HYPOMYELINATION; DDCH","url":"https://www.omim.org/entry/300475"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BCAP31"},"hgnc":{"alias_symbol":["DXS1357E","BAP31","6C6-Ag","CDM"],"prev_symbol":[]},"alphafold":{"accession":"P51572","domains":[{"cath_id":"-","chopping":"2-150","consensus_level":"high","plddt":88.6927,"start":2,"end":150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51572","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51572-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51572-F1-predicted_aligned_error_v6.png","plddt_mean":84.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BCAP31","jax_strain_url":"https://www.jax.org/strain/search?query=BCAP31"},"sequence":{"accession":"P51572","fasta_url":"https://rest.uniprot.org/uniprotkb/P51572.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51572/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51572"}},"corpus_meta":[{"pmid":"12668660","id":"PMC_12668660","title":"Caspase cleavage 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Caspase-8 and caspase-1 (but not caspase-3) cleave BAP31 at two identical AAVD.G caspase recognition sites in vitro, generating a p20 fragment. Bax prevents Bcl-2 from associating with the complex. The p20 fragment induces apoptosis when expressed ectopically.\",\n      \"method\": \"Co-immunoprecipitation in co-transfected 293T cells; in vitro caspase cleavage assays; ectopic expression of p20 fragment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, in vitro enzymatic assay, mutagenesis, functional ectopic expression; foundational paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"9334338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"BAP31 preferentially associates with membrane IgD but not IgM, and specific amino acids in the transmembrane sequence of the IgD heavy chain (delta-m chain) are critical for binding to BAP29/BAP31, as determined by mutational analysis.\",\n      \"method\": \"Mutagenesis of IgD transmembrane domain; co-immunoprecipitation; cloning and sequence analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutational analysis with Co-IP; single lab but two orthogonal methods\",\n      \"pmids\": [\"8612576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"BAP31 controls ER-to-Golgi anterograde transport of cellubrevin; BAP31 and cellubrevin interact via their transmembrane regions (sensitive to high ionic strength); truncation of the BAP31 cytoplasmic tail prevents ER export of cellubrevin but not of the transferrin receptor. BAP31 localizes to the ER and a paranuclear vesicular compartment dependent on intact microtubules.\",\n      \"method\": \"Co-immunoprecipitation from fibroblast detergent extracts; affinity pulldown with recombinant cellubrevin; immunocytochemistry; BAP31 cytoplasmic-tail truncation mutants; nocodazole treatment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, pulldown, dominant-negative truncation mutant with specific cargo readout; replicated conceptually across multiple subsequent studies\",\n      \"pmids\": [\"9396746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The predicted death effector homology (vDED) domain in the cytosolic region of BAP31 interacts with CED-4, which in turn contributes to recruitment of procaspase-8 to the BAP31 complex. Bcl-XL binds directly but weakly to the transmembrane region of BAP31, and indirectly and cooperatively to the cytosolic domain dependent on procaspase-8 and CED-4. CED-4Δc displaces Bcl-XL from the complex.\",\n      \"method\": \"Co-immunoprecipitation in co-transfected human cells; domain-mapping experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, single lab, two orthogonal approaches\",\n      \"pmids\": [\"9452422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Caspase-resistant BAP31 (crBAP31, with AAVD→AAVA mutations) blocks Fas-mediated cytochrome c release from mitochondria and membrane fragmentation, demonstrating that uncleaved full-length BAP31 is an inhibitor of these apoptotic events. The data reveal unexpected ER-mitochondria crosstalk during Fas apoptosis mediated through BAP31 cleavage status.\",\n      \"method\": \"Stable expression of caspase-resistant BAP31 mutant in KB epithelial cells; Fas stimulation; measurement of cytochrome c release, caspase activation, phosphatidylserine redistribution, mitochondrial membrane potential\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function (caspase-resistant mutant) with multiple orthogonal apoptotic readouts; foundational paper independently replicated\",\n      \"pmids\": [\"10958671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BAP31 controls expression and ER-membrane retention of CFTR; antisense inhibition of BAP31 increases CFTR expression and enables cAMP-activated Cl⁻ currents in ΔF508-CFTR-expressing CHO cells; coexpression of CFTR with BAP31 attenuates cAMP-activated Cl⁻ currents in Xenopus oocytes. BAP31 and CFTR colocalize in the cytosol.\",\n      \"method\": \"Antisense knockdown of BAP31 in CHO cells; co-expression in Xenopus oocytes with electrophysiology; immunofluorescence colocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function knockdown plus electrophysiological functional readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"11274174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Procaspase-8L, characterized by an N-terminal extension (Nex) domain, is selectively recruited to the BAP31 complex at the ER via its Nex domain. Gene deletion of BAP31 and the related BAP29 impairs processing of procaspase-8L in response to E1A by a FADD-independent, BCL-2-inhibitable mechanism, and curtails downstream caspase activation and cell death.\",\n      \"method\": \"BAP31/BAP29 gene deletion in mouse cells; dominant-negative Nex-domain mutant; co-immunoprecipitation; caspase activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene deletion, dominant-negative, Co-IP, functional caspase assays in one study; clear epistatic placement\",\n      \"pmids\": [\"11917123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The p20 caspase-8 cleavage fragment of BAP31 triggers Ca²⁺ release from the ER, concomitant Ca²⁺ uptake into mitochondria, and mitochondrial recruitment of Drp1, resulting in mitochondrial fission. Inhibition of Drp1 or ER-mitochondrial Ca²⁺ signaling prevents p20-induced fission. p20 sensitizes mitochondria to caspase-8-induced cytochrome c release.\",\n      \"method\": \"Adenoviral expression of p20 BAP31 fragment; Ca²⁺ imaging; mitochondrial morphology assays; Drp1 dominant-negative inhibition; cytochrome c release assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Ca²⁺ imaging, morphology, inhibition of Drp1, cytochrome c release) in single rigorous study; independently replicated concept\",\n      \"pmids\": [\"12668660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Full-length BAP31, in association with the putative ER ion channel protein A4 (a constitutive BAP31-binding partner identified by split-ubiquitin yeast two-hybrid), is a direct inhibitor of BAX/BAK oligomerization and cytochrome c release downstream of caspase-8 activation, acting independently of its ability to generate p20.\",\n      \"method\": \"Split-ubiquitin yeast two-hybrid screen; co-immunoprecipitation; reconstitution in Bap31-null mouse cells; FKBPcasp8 inducible system; cytochrome c release assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid identification plus Co-IP confirmation, null-cell reconstitution, inducible caspase system; multiple methods in one study\",\n      \"pmids\": [\"12529377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BAP31 specifically associates with nonmuscle myosin heavy chain B and nonmuscle gamma-actin (components of the actomyosin cytoskeleton), and Fas-induced apoptosis releases these associations, potentially contributing to membrane remodelling during apoptosis.\",\n      \"method\": \"Capillary LC-MS/MS characterization of BAP31 immunocomplex from HepG2 cells; co-immunoprecipitation\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — MS identification confirmed by Co-IP; single lab\",\n      \"pmids\": [\"12605685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BAP29/BAP31 form high-molecular-weight complexes in the ER that retain membrane-bound IgD lacking its Ig-α/Ig-β subunits. In Drosophila S2 cells, surface appearance of IgD is prevented by coexpression of BAP29 and BAP31. The retention mechanism is true ER retention, not retrieval from a post-ER compartment.\",\n      \"method\": \"Blue native PAGE; co-immunoprecipitation; heterologous expression in Drosophila S2 cells; immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blue native PAGE, heterologous system, Co-IP; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"12886015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BAP31 specifically binds to CD11b/CD18 (beta-2 integrin) via the cytoplasmic tail of BAP31; the interaction is not dependent on divalent cations or the CD11b I-domain. BAP31 and CD11b/CD18 colocalize in neutrophil secondary granules and both redistribute to the plasma membrane upon fMLP stimulation.\",\n      \"method\": \"Monoclonal antibody co-precipitation; co-immunoprecipitation; GST-fusion binding assays; immunolocalization; subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, GST pulldown, domain mapping, colocalization; single lab\",\n      \"pmids\": [\"15294914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BAP31 is required for stability of a novel ER integral membrane protein PTPLB; in Bap31-null mouse cells PTPLB turns over more rapidly via proteasomal degradation, whereas reconstitution with human BAP31 maintains PTPLB levels, consistent with a chaperone/quality control function for BAP31 in the ER membrane.\",\n      \"method\": \"Split-ubiquitin cDNA library screen; Bap31-null mouse cells reconstituted with BAP31; proteasome inhibitor experiments; turnover assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null reconstitution plus split-ubiquitin identification; single lab, two orthogonal methods\",\n      \"pmids\": [\"15024066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BAP31 is required for cell-surface expression of tetraspanins CD9 and CD81; in Bap31-null mouse cells, CD9 and CD81 surface levels are reduced, integrin-mediated cell adhesion to extracellular matrix is impaired under serum stress, and cells are sensitized to apoptosis. Reconstitution of BAP31 restores surface tetraspanin levels and integrin-mediated survival. The p20 BAP31 cleavage product inhibits egress of tetraspanins and integrin-mediated cell attachment.\",\n      \"method\": \"Bap31-null mouse cells; reconstitution with wild-type BAP31; p20 BAP31 ectopic expression; flow cytometry for surface tetraspanins; adhesion and apoptosis assays; antibody antagonism of CD9/integrins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null cells, reconstitution, p20 expression, multiple orthogonal cellular assays in one study\",\n      \"pmids\": [\"15946936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BAP31 interacts with cytochrome P450 2C2 in the ER via transmembrane domain interactions (shown by bimolecular fluorescence complementation and Co-IP); BAP31 depletion causes redistribution of P450 2C2 from the ER to nuclear membrane and cell surface, and increases P450 2C2 expression levels, indicating BAP31 retains P450 2C2 in the ER.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC); co-immunoprecipitation; siRNA knockdown of BAP31; Bap31-null ES cells reconstituted with BAP31; immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BiFC plus Co-IP plus null-cell reconstitution; single lab\",\n      \"pmids\": [\"16332681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BAP31 enhances ER export of peptide-loaded MHC class I molecules; overexpression of BAP31 increases surface class I levels by accelerating ER export and stabilizing exported molecules. BAP31 may also retrieve peptide-depleted class I from post-ER acidic compartments. Overexpression of the homolog BAP29 decreases surface class I levels.\",\n      \"method\": \"Transfection of YFP-Bap31 chimeras in HeLa cells; flow cytometry for surface MHC class I; pulse-chase experiments; comparison with BAP29 overexpression\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — overexpression with functional surface-level readout, pulse-chase kinetics; single lab\",\n      \"pmids\": [\"17056546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BAP31 is an itinerant ER protein that cycles between the peripheral ER and a juxtanuclear ER-related quality control compartment; this cycling depends on microtubules and dynein-dynactin function. The third and second transmembrane domains of BAP31 are principally responsible for movement to and recycling from the juxtanuclear region, respectively. Sar1p and Arf1 mutants affect BAP31 cycling.\",\n      \"method\": \"Live-cell fluorescence imaging with GFP-Bap31; FRAP; dominant-negative Sar1p and Arf1 mutants; microtubule depolymerization (nocodazole); dynein-dynactin disruption; transmembrane domain deletion mutants\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging, FRAP, multiple dominant-negative mutants, transmembrane domain mapping; multiple orthogonal methods in one study\",\n      \"pmids\": [\"18287538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BAP31 associates with two components of the Sec61 preprotein translocon (Sec61β and TRAM); BAP31 associates with the N-terminus of newly synthesized ΔF508-CFTR and promotes its retrotranslocation and degradation by the 26S proteasome. Depletion of BAP31 reduces proteasomal degradation of ΔF508 and allows it to reach the cell surface. BAP31 also physically and functionally associates with the Derlin-1 dislocation complex in the ΔF508 degradation pathway.\",\n      \"method\": \"Co-immunoprecipitation; siRNA depletion of BAP31; pulse-chase degradation assays; proteasome inhibition; cell-surface biotinylation; Derlin-1 association\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with multiple partners, siRNA KD, pulse-chase, cell-surface assay; multiple orthogonal methods; published in high-tier journal\",\n      \"pmids\": [\"18555783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BAP31 interacts with HPV E5 proteins (HPV16 and HPV31); interaction confirmed by split-ubiquitin yeast two-hybrid and coimmunoprecipitation. Amino acids in the extreme C-terminus of E5 are required for stabilizing the interaction. Deletion of C-terminal E5 residues in complete HPV31 genomes impairs proliferative capacity of keratinocytes upon differentiation; siRNA knockdown of Bap31 similarly reduces this proliferative ability.\",\n      \"method\": \"Split-ubiquitin yeast two-hybrid screen; co-immunoprecipitation; E5 C-terminal deletion mutants in HPV31 genomes; siRNA knockdown of Bap31; colocalization (immunofluorescence)\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — split-ubiquitin plus Co-IP confirmation, mutational analysis, functional siRNA; single lab\",\n      \"pmids\": [\"18684816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BAP31 clusters with MHC class I (HLA-A2) in the ER and traffics with it to the ERGIC via export vesicles; FRET between BAP31 and HLA-A2 and forward traffic increase when class I molecules are loaded with peptide. Overexpression of BAP29 blocks BAP31-mediated forward traffic of class I.\",\n      \"method\": \"FRET (Förster resonance energy transfer); quantitative fluorescence microscopy; peptide pulse experiments; BAP29 overexpression\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET and quantitative imaging with functional peptide-loading readout; single lab\",\n      \"pmids\": [\"19342655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fis1 (outer mitochondrial membrane fission protein) interacts with BAP31 at the ER membrane to form the 'ARCosome' platform spanning the mitochondria-ER interface. This complex facilitates cleavage of BAP31 into pro-apoptotic p20BAP31. The BAP31 vDED domain is required for recruitment of procaspase-8 to the Fis1-BAP31 complex, and this recruitment is required for procaspase-8 activation. Activation triggers ER Ca²⁺ release establishing a feedback loop to activate mitochondria.\",\n      \"method\": \"Co-immunoprecipitation; Fis1 and BAP31 overexpression/knockdown; procaspase-8 recruitment assays; Ca²⁺ release measurements; BAP31 vDED domain mutants\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, domain mutants, functional caspase activation, Ca²⁺ signaling; multiple orthogonal methods; independently replicated concept\",\n      \"pmids\": [\"21183955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The yeast BAP31 homologs Yet1p and Yet3p form a complex (Yet complex) important for subunit stability and proper ER localization; the Yet complex is not efficiently packaged into COPII vesicles and is not an ER export receptor. Instead, a fraction of the Yet complex associates with the Sec61 ER translocation apparatus (Sec complex), and this association increases under ER stress and decreases when translocation substrates are depleted.\",\n      \"method\": \"Co-immunoprecipitation; COPII vesicle packaging assays; ER stress induction; genetic mutant analysis; protein stability assays in yeast\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast ortholog study; Co-IP, vesicle packaging assay, genetic epistasis; single lab\",\n      \"pmids\": [\"20378542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BAP31 and the ER lumenal chaperone BiP are both required for dislocation of SV40 from the ER to the cytosol; both proteins colocalize with the virus in discrete foci. siRNA knockdown of BAP31 or BiP prevents ER-to-cytosol dislocation of SV40 particles. The ERAD machinery assists virus transport across the ER membrane.\",\n      \"method\": \"siRNA screen; immunofluorescence colocalization; SV40 infection and dislocation assays; siRNA knockdown functional validation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA screen with functional validation of dislocation assay; colocalization; published in high-tier journal with clear mechanistic readout\",\n      \"pmids\": [\"21947079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDIP1 (a proapoptotic p53 target) interacts with BAP31 at the ER membrane; upon ER stress CDIP1 is induced and enhances its association with BAP31. CDIP1 binding to BAP31 is required for BAP31 cleavage during ER stress and for BAP31-Bcl-2 association. The CDIP1-BAP31 complex recruits Bcl-2, promotes tBid and caspase-8 activation, and BAX oligomerization. CDIP1 knockout in mice impairs ER-stress-mediated apoptosis.\",\n      \"method\": \"Co-immunoprecipitation; ER stress induction; CDIP1 knockout mice; BAP31 cleavage assays; caspase-8 activation assays; BAX oligomerization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, genetic KO mice, multiple functional apoptotic readouts; multiple orthogonal methods\",\n      \"pmids\": [\"24139803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in BCAP31 in humans result in ER morphology alteration and Golgi disorganization in primary fibroblasts, demonstrating that BAP31 is required for ER-to-Golgi crosstalk. Constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors (in contrast to transient RNAi experiments).\",\n      \"method\": \"Patient-derived primary fibroblasts with loss-of-function BCAP31 mutations; immunofluorescence for ER/Golgi morphology; UPR marker assays; Western blot for cell-death effectors\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient cell loss-of-function, multiple morphological and biochemical readouts; single study but human genetics validation\",\n      \"pmids\": [\"24011989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The cytoplasmic variant of death effector domain (vDED) of BAP31 forms a dimeric parallel coiled coil (crystal structure determined), with no structural similarity to canonical DED domains. Solution studies confirm this coiled-coil conformation and suggest an additional C-terminal alpha-helical coiled-coil domain. BAP29 vDED is partially unfolded at neutral pH in vitro.\",\n      \"method\": \"X-ray crystallography (two crystal forms); circular dichroism; size-exclusion chromatography; solution biophysical characterization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure solved plus orthogonal solution biophysical validation; single lab but direct structural determination\",\n      \"pmids\": [\"23967155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BAP31 directly interacts with the RSV small hydrophobic (SH) protein; the C-terminal endodomain of BAP31 and SH protein interact directly as shown by NMR titration of purified proteins in detergent micelles, and SH protein pulls down endogenous BAP31.\",\n      \"method\": \"Membrane-based yeast two-hybrid; co-immunoprecipitation (pull-down); NMR titration of purified proteins\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro NMR direct binding assay plus pull-down; single lab\",\n      \"pmids\": [\"25854864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BAP31 on the cell surface of human embryonic stem cells exposes its C-terminal domain extracellularly, representing a novel membrane topology distinct from its canonical ER orientation (where C-terminus faces cytosol). Epitope mapping with deletion mutants confirmed that both cytoplasm-facing and surface-exposed C-terminal residues 208–217 are recognized by antibodies.\",\n      \"method\": \"Monoclonal antibody epitope mapping; GST-fused BAP31 serial C-terminal deletion mutants; immunofluorescence on hESCs and mESCs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epitope mapping via antibodies and deletion constructs; single lab, no functional consequence established\",\n      \"pmids\": [\"26102500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BAP31 is required for T cell activation through TCR signaling; BAP31 conditional knockdown in mouse thymus reduces T cell numbers and proliferation, decreases phosphorylation of ZAP70, Lck, Lat (upstream TCR), and Akt, GSK, JNK, ERK (downstream), and reduces TCRα/β/CD3 expression and cytokines (IL-2, IFN-γ, IL-6, TNF-α).\",\n      \"method\": \"Conditional BAP31 knockdown mouse (Cre/loxP); T cell proliferation assays; Western blot for phosphorylated TCR signaling components; flow cytometry for surface markers; ELISA for cytokines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse model with multiple TCR pathway phosphorylation readouts; single lab\",\n      \"pmids\": [\"28333124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BAP31 is a binding partner of RTN3 and positively regulates RTN3 monomer stability; BAP31 knockout in hippocampal neurons increases RTN3 aggregate formation and decreases RTN3 monomer availability, enhancing BACE1-mediated APP processing and amyloid-β plaque deposition in an Alzheimer's disease mouse model.\",\n      \"method\": \"Co-immunoprecipitation; conditional BAP31 KO mice crossed with APP/PS1 AD model mice; Western blot for RTN3 monomer vs. aggregates; BACE1 activity; amyloid plaque quantification\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus conditional KO in disease model; multiple readouts; single lab\",\n      \"pmids\": [\"30596517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hepatocyte-specific deletion of BAP31 increases SREBP1C expression and activity; immunoprecipitation shows BAP31 interacts with SREBP1C and INSIG1; BAP31 deletion reduces INSIG1 expression, suggesting BAP31 regulates SREBP1C activity by modulating INSIG1 levels, leading to increased hepatic lipid accumulation and ER stress.\",\n      \"method\": \"Hepatocyte-specific conditional BAP31 KO mice; high-fat diet challenge; co-immunoprecipitation; Western blot for SREBP1C targets; hepatic lipid assays; ER stress markers\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mice plus Co-IP; multiple metabolic and signaling readouts; single lab\",\n      \"pmids\": [\"29113994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAP31 interacts with the mitochondrial import protein Tom40 within ER-mitochondria contact sites; the BAP31-Tom40 complex facilitates translocation of NDUFS4 (a complex I subunit) from the cytosol to mitochondria. Disruption of the BAP31-Tom40 complex inhibits mitochondrial complex I activity and oxygen consumption.\",\n      \"method\": \"Co-immunoprecipitation; NDUFS4 translocation assays; mitochondrial complex I activity assays; oxygen consumption measurements; BAP31 knockdown\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, protein translocation assay, mitochondrial functional assays; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31206022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAP31 inhibits autophagy by forming a BAP31-STX17 protein complex; loss of BAP31 stimulates tumor growth under metabolic stress conditions in vivo and enhances invasion activity. BAP31 acts to suppress ER stress adaptation and suppress autophagy.\",\n      \"method\": \"Co-immunoprecipitation of BAP31-STX17 complex; BAP31 KO cells; autophagy assays; xenograft tumor models; invasion assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus in vivo tumor model with functional readouts; single lab\",\n      \"pmids\": [\"31671609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BCAP31 interacts with EGFR and acts as an inhibitor of ligand-independent EGFR recycling, sustaining EGFR autophosphorylation and activation of downstream signaling. BCAP31 knockdown reduces TNBC tumor growth.\",\n      \"method\": \"Co-immunoprecipitation; EGFR recycling/trafficking assays; phosphorylation assays; BCAP31 knockdown in vitro and in vivo\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus EGFR trafficking functional assay; single lab\",\n      \"pmids\": [\"31588230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAP31 specifically interacts with and regulates the proteasomal degradation of p27kip1 (cyclin kinase inhibitor); an intrabody (VH-D1) against BAP31 inhibits p27kip1 proteasome degradation, possibly by blocking BAP31-p27kip1 interaction, leading to suppressed proliferation and increased apoptosis in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; intrabody expression; proteasome inhibitor assays; cell proliferation and apoptosis assays; xenograft mouse model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus functional intrabody blockade; single lab\",\n      \"pmids\": [\"30338855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAP31 deficiency in microglia upregulates IRAK1 protein levels, which in turn increases NF-κB p65 and c-Jun nuclear translocation and transcriptional activity, enhancing LPS-induced proinflammatory cytokine production. Knockdown of IRAK1 or an IRAK1 inhibitor reverses these effects.\",\n      \"method\": \"BAP31 conditional knockdown mice; BV2 cell knockdown; Western blot for IRAK1, phospho-NF-κB, phospho-c-Jun; ELISA for cytokines; immunofluorescence for NF-κB translocation; LPS-induced cognitive impairment model\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mice plus cellular knockdown, epistasis via IRAK1 inhibition; single lab\",\n      \"pmids\": [\"31883536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BAP31 directly binds to SERPINE2 (serpin family E member 2); co-immunoprecipitation and immunofluorescence assays confirm the interaction; BAP31 promotes HCC tumor cell proliferation by stabilizing SERPINE2 and activating downstream Erk1/2 and p38 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence; RNA-seq; BAP31 knockdown/overexpression; tumor xenografts\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus RNA-seq with functional validation; single lab\",\n      \"pmids\": [\"33363167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BAP31 interacts with VDAC1 at the ER-mitochondria interface and affects VDAC1 oligomerization and polyubiquitination; knockdown of BAP31 increases lipid peroxidation and promotes ferroptosis and G1/S arrest in gastric cancer. HNF4A binds the BAP31 promoter and increases its transcription.\",\n      \"method\": \"Co-immunoprecipitation; VDAC1 oligomerization assays; ubiquitination assays; ChIP for HNF4A at BAP31 promoter; BAP31 knockdown; ferroptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, oligomerization assay, ChIP; single lab with multiple methods\",\n      \"pmids\": [\"37296105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BAP31 interacts with Perilipin1 via its C-terminal cytoplasmic domain on the surface of lipid droplets; BAP31 depletion represses Perilipin1 proteasomal degradation, leading to enhanced Perilipin1 expression, blocked lipid droplet degradation, supersized lipid droplet formation, impaired lipolysis, and altered adipogenesis.\",\n      \"method\": \"Co-immunoprecipitation; BAP31-adipocyte-specific KO mice; adipocyte differentiation of MEFs; lipolysis assays; proteasome inhibitor experiments; lipid droplet imaging\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mice, Co-IP domain mapping, functional lipolysis and adipogenesis assays; single lab\",\n      \"pmids\": [\"37063427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sirtuin 2 deacetylates BAP31 specifically at lysine 158 (K158); this deacetylation stabilizes BAP31 expression. Loss of sirtuin 2 reduces BAP31 expression. Carnosol upregulates sirtuin 2, which in turn deacetylates BAP31 to attenuate ER stress and hepatocyte apoptosis in alcoholic liver disease.\",\n      \"method\": \"Sirtuin 2 knockdown; site-specific acetylation mapping at K158; Western blot; alcohol-induced liver injury mouse model\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM identification plus in vivo loss-of-function; single lab\",\n      \"pmids\": [\"39887347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structure of the Fis1 cytosolic domain bound to the C-terminal vDED region of BAP31 reveals that the Bap31_vDED region engages the convex surface of Fis1's tetratricopeptide repeat (TPR) domain. One Fis1 structure features an N-terminal 'Fis1 arm' conformation suggestive of an autoinhibitory function.\",\n      \"method\": \"X-ray crystallography of Fis1 alone (two conformations) and Fis1-Bap31_vDED co-complex\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of co-complex directly defining the Fis1-Bap31 interaction surface; single study but direct structural determination\",\n      \"pmids\": [\"40770055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PINK1 interacts with BAP31 and phosphorylates it at serine 142 (Ser142). PINK1-mediated phosphorylation of BAP31 is required for its neuroprotective effects against ER stress-mediated apoptosis; phosphomimetic BAP31-S142E strengthens protection while phospho-dead BAP31-S142A abolishes it.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis (S142A, S142E phosphomimetics); ER stress assays; PINK1 overexpression/knockdown; in vitro and in vivo neuronal models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phospho-site mutagenesis with functional apoptosis readout; single lab\",\n      \"pmids\": [\"41022756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BCAP31 directly interacts with PINK1 and promotes PINK1 phosphorylation; BAP31 depletion reduces phosphorylated PINK1 levels, thereby inhibiting PINK1/Parkin-mediated mitophagy, leading to increased mitochondrial ROS, NF-κB activation, and alveolar epithelial cell apoptosis in acute lung injury.\",\n      \"method\": \"Co-immunoprecipitation (BAP31-PINK1); BCAP31 transgenic and conditional KO mice; mitophagy assays; mitochondrial ROS measurement; LPS-induced ALI model\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, transgenic and KO mice, mitophagy functional assays; single lab\",\n      \"pmids\": [\"39381793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAP31 is exploited by Legionella pneumophila; a Legionella effector Lpg1152 binds to BAP31. BAP31 together with Rab10 and Rab4 GTPases facilitates transitioning the Legionella-containing vacuole (LCV) from smooth ER to rough ER association. Optimal Legionella growth requires both BAP31 and Lpg1152.\",\n      \"method\": \"Co-immunoprecipitation of Lpg1152 with BAP31; BAP31 knockdown; Rab10/Rab4 knockdown; LCV morphology imaging; bacterial growth assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, siRNA KD with functional LCV and bacterial growth readouts; single lab\",\n      \"pmids\": [\"39661521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BAP31 regulates ICAM-1 and VCAM-1 expression in endothelial cells via the MyD88/TRAF6-TAK1/NF-κB and PI3K/Akt signaling cascades; BAP31 knockdown deactivates these cascades, reducing NF-κB nuclear translocation and reducing neutrophil-endothelial cell adhesion in ALI.\",\n      \"method\": \"shBAP31 endothelial cell lines; endothelial-specific conditional BAP31 KO mice; luciferase reporter assays for ICAM-1/VCAM-1 promoters; ChIP; intravital microscopy; Western blot for NF-κB pathway proteins\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mice, ChIP, luciferase reporter, multiple signaling pathway readouts; single lab\",\n      \"pmids\": [\"36549351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BAP31 promotes N-glycosylation of EpCAM by affecting the Sec61 translocation channel; the amino acid region 165-205 of BAP31 is important for this function. An intrabody (VH-F12) against this region inhibits EpCAM glycosylation.\",\n      \"method\": \"EpCAM glycosylation mutants (N76/111/198A); BAP31 C-terminal deletion constructs; intrabody expression; Western blot; Co-immunoprecipitation with Sec61\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — glycosylation mutants, BAP31 domain mapping, intrabody functional blockade; single lab\",\n      \"pmids\": [\"37834237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BAP31 interacts with ELAVL1 (an RNA-binding protein) and promotes its maturation; ELAVL1 binds to the 3'UTR of SPINK6 mRNA to stabilize its expression. BAP31 silencing inhibits HCC cell invasion/migration and recovers cell polarity via reduction of SPINK6.\",\n      \"method\": \"IP-MS (immunoprecipitation mass spectrometry); immunofluorescence; RNA immunoprecipitation (RIP); RNA-FISH; RNA stability assays; luciferase reporter assay; in vivo metastasis model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus RIP plus RNA stability with functional metastasis readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39990675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BAP31 interacts with PCMT1, a direct negative regulator of MST1 kinase; BAP31 knockdown activates MST1 and inhibits YAP transcription factor, suppressing breast cancer stemness via the Hippo pathway.\",\n      \"method\": \"Co-immunoprecipitation (BAP31-PCMT1); BAP31 knockdown; MST1 activity and YAP phosphorylation assays; tumor sphere formation; xenograft models\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with functional pathway readout; single lab, limited mechanistic depth\",\n      \"pmids\": [\"40332113\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BAP31 is a polytopic ER integral membrane protein that functions as a broad-specificity chaperone/cargo receptor (controlling ER retention, export, retrotranslocation and ERAD of client transmembrane proteins including CFTR, MHC class I, CD9/CD81, cellubrevin, EGFR, SERPINE2, and others), a scaffold for apoptosis regulation at ER-mitochondria contact sites (forming complexes with Bcl-2/Bcl-XL, procaspase-8L, Fis1, and CDIP1; being cleaved by caspase-8 into pro-apoptotic p20 that triggers ER Ca²⁺ release, Drp1-dependent mitochondrial fission, and cytochrome c release), and a MAM tether that bridges mitochondria and ER via Tom40 to support mitochondrial complex I assembly, with its function further regulated by PINK1-mediated phosphorylation at Ser142 and sirtuin 2-mediated deacetylation at Lys158.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BCAP31 (BAP31) is a polytopic ER integral membrane protein that functions as a broad-specificity chaperone and quality-control factor governing ER retention, export, and ERAD of client transmembrane proteins, and as a scaffold that couples the ER to mitochondria for both apoptotic and metabolic signaling [#0, #2, #17]. As a cargo/retention factor it controls ER-to-Golgi anterograde transport (cellubrevin export depends on its cytoplasmic tail) [#2], retains immature or unassembled clients in the ER (membrane IgD, cytochrome P450 2C2) [#10, #14], promotes export and stabilization of peptide-loaded MHC class I [#15, #19], and supports surface delivery of tetraspanins CD9/CD81 to sustain integrin-mediated adhesion and survival [#13]; it itinerates between peripheral ER and a juxtanuclear quality-control compartment in a microtubule- and dynein-dynactin-dependent manner [#16]. Through association with the Sec61 translocon components Sec61β/TRAM and the Derlin-1 dislocation complex, BAP31 directs retrotranslocation and proteasomal degradation of misfolded clients such as ΔF508-CFTR [#17]. BAP31 is also a central apoptosis regulator: full-length BAP31 forms a complex with Bcl-2/Bcl-XL and procaspase-8(L) and inhibits BAX/BAK oligomerization and cytochrome c release, while caspase-8/caspase-1 cleavage generates a pro-apoptotic p20 fragment that triggers ER Ca²⁺ release, Drp1-dependent mitochondrial fission, and sensitization to cytochrome c release [#0, #4, #6, #7, #8]. This apoptotic platform is assembled at ER-mitochondria contacts with Fis1 (the 'ARCosome') and is engaged during ER stress through CDIP1 [#20, #23], with the BAP31 vDED region — structurally a coiled coil — directly binding the TPR domain of Fis1 [#25, #40]. At ER-mitochondria contacts BAP31 additionally tethers the mitochondrial import receptor Tom40 to deliver the complex I subunit NDUFS4 and support oxidative phosphorylation [#31]. Loss-of-function mutations in BCAP31 in humans disrupt ER and Golgi morphology, establishing its requirement for ER-to-Golgi homeostasis [#24]. Its activity is modulated by post-translational modification, including PINK1-mediated phosphorylation at Ser142 and sirtuin 2-mediated deacetylation at Lys158 [#41, #39].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established BAP31 as an ER membrane scaffold linking Bcl-2 family survival proteins to caspase-8, defining a caspase-cleavable substrate whose p20 product is itself pro-apoptotic.\",\n      \"evidence\": \"Reciprocal Co-IP in 293T cells, in vitro caspase cleavage with mutagenesis of AAVD sites, and ectopic p20 expression\",\n      \"pmids\": [\"9334338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the physiological trigger for cleavage in intact cells\", \"Did not localize the activity to ER-mitochondria contacts\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified BAP31/BAP29 as transmembrane-domain-selective binding partners of membrane immunoglobulin, first hinting at a cargo/retention role for ER-resident clients.\",\n      \"evidence\": \"Mutagenesis of the IgD delta-m transmembrane domain with Co-IP\",\n      \"pmids\": [\"8612576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence (retention vs export) of the IgD interaction not yet defined\", \"Generality beyond IgD untested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated that BAP31 actively controls ER export of a specific cargo, distinguishing a chaperone/export-receptor function from generic ER residence.\",\n      \"evidence\": \"Co-IP and recombinant pulldown with cellubrevin plus cytoplasmic-tail truncation mutants and nocodazole treatment in fibroblasts\",\n      \"pmids\": [\"9396746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the COPII/export machinery BAP31 engages\", \"Cargo selectivity rules not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed that cleavage status converts BAP31 from a survival factor to a death signal, revealing ER-mitochondria crosstalk in Fas apoptosis.\",\n      \"evidence\": \"Stable caspase-resistant crBAP31 mutant in KB cells with cytochrome c release and mitochondrial readouts\",\n      \"pmids\": [\"10958671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular relay from ER cleavage to mitochondria not yet identified\", \"Identity of mitochondrial effectors unknown at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed BAP31/BAP29 epistatically upstream of procaspase-8L processing via a FADD-independent, Bcl-2-inhibitable route, defining a death-receptor-independent caspase-8 activation platform.\",\n      \"evidence\": \"BAP31/BAP29 gene deletion in mouse cells, dominant-negative Nex domain, Co-IP and caspase assays\",\n      \"pmids\": [\"11917123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial assembly of the platform not yet resolved\", \"Stimulus specificity beyond E1A not fully mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved how p20 reaches mitochondria, showing it drives ER Ca²⁺ release and Drp1-dependent fission that sensitizes mitochondria to cytochrome c release.\",\n      \"evidence\": \"Adenoviral p20 expression with Ca²⁺ imaging, mitochondrial morphology, Drp1 dominant-negative and cytochrome c assays\",\n      \"pmids\": [\"12668660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of p20 at the ER/mitochondria not defined\", \"How Ca²⁺ release is gated by p20 unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the anti-apoptotic arm of full-length BAP31 as direct inhibition of BAX/BAK oligomerization, in partnership with the A4 ER channel protein and independent of p20 generation.\",\n      \"evidence\": \"Split-ubiquitin Y2H, Co-IP, Bap31-null reconstitution and inducible FKBPcasp8 cytochrome c assays\",\n      \"pmids\": [\"12529377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which BAP31 restrains BAX/BAK not structurally defined\", \"Role of A4 channel activity unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Extended BAP31 quality control to disease-relevant transmembrane clients, showing it retains and limits surface delivery of CFTR.\",\n      \"evidence\": \"Antisense knockdown in CHO cells, Xenopus oocyte co-expression electrophysiology and colocalization (combined 2001 finding)\",\n      \"pmids\": [\"11274174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not distinguish retention from degradation at this stage\", \"ERAD machinery not yet linked\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Broadened BAP31's role to active ER membrane protein quality control by showing it stabilizes a client (PTPLB) against proteasomal turnover.\",\n      \"evidence\": \"Split-ubiquitin cDNA screen, Bap31-null reconstitution and proteasome-inhibitor turnover assays\",\n      \"pmids\": [\"15024066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stabilization reflects folding assistance or degradation shielding unclear\", \"Recognition determinants on clients unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected BAP31 quality control to cell physiology by linking tetraspanin surface delivery to integrin-mediated adhesion and apoptotic sensitivity.\",\n      \"evidence\": \"Bap31-null cells, reconstitution, p20 expression, flow cytometry and adhesion/apoptosis assays\",\n      \"pmids\": [\"15946936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding to CD9/CD81 versus indirect chaperoning not fully resolved\", \"Mechanism of p20 inhibition of egress unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed BAP31 promotes ER export and stabilization of peptide-loaded MHC class I, with the paralog BAP29 acting oppositely, refining its export-receptor function.\",\n      \"evidence\": \"YFP-Bap31 chimeras, surface class I flow cytometry and pulse-chase in HeLa cells (with 2009 FRET follow-up)\",\n      \"pmids\": [\"17056546\", \"19342655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of peptide-loading-dependent recognition undefined\", \"Quantitative contribution to antigen presentation in vivo not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mechanistically integrated BAP31 into ERAD by showing it associates with Sec61β/TRAM and the Derlin-1 complex to drive retrotranslocation and degradation of ΔF508-CFTR.\",\n      \"evidence\": \"Co-IP with translocon/dislocation components, siRNA depletion, pulse-chase and surface biotinylation\",\n      \"pmids\": [\"18555783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BAP31 selects clients for export versus dislocation not resolved\", \"Stoichiometry within the dislocation complex unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the itinerant cycling behavior and transmembrane-domain determinants underlying BAP31 trafficking between peripheral and juxtanuclear ER compartments.\",\n      \"evidence\": \"Live GFP-Bap31 imaging, FRAP, dominant-negative Sar1p/Arf1, nocodazole, dynein-dynactin disruption and TMD deletions\",\n      \"pmids\": [\"18287538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of juxtanuclear cycling in quality control not established\", \"Cargo coupling to the cycling pathway unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Localized the apoptotic platform to ER-mitochondria contacts by identifying the Fis1-BAP31 'ARCosome' that recruits and activates procaspase-8 via the vDED domain.\",\n      \"evidence\": \"Co-IP, Fis1/BAP31 overexpression and knockdown, vDED mutants and Ca²⁺ release measurements\",\n      \"pmids\": [\"21183955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that nucleates ARCosome assembly not defined\", \"Quantitative Ca²⁺ feedback parameters unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked ER stress to the BAP31 death platform by showing the p53 target CDIP1 binds BAP31, enables its cleavage, and recruits Bcl-2 to drive apoptosis.\",\n      \"evidence\": \"Co-IP, ER stress induction, CDIP1 knockout mice, BAP31 cleavage, caspase-8 and BAX oligomerization assays\",\n      \"pmids\": [\"24139803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDIP1 binding licenses cleavage mechanistically unclear\", \"Interplay with the Fis1 ARCosome not integrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided structural insight that the BAP31 vDED is not a canonical DED but a parallel coiled coil, reframing how it scaffolds caspase recruitment.\",\n      \"evidence\": \"X-ray crystallography of the vDED with CD and SEC solution validation\",\n      \"pmids\": [\"23967155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full caspase-8/CED-4-bound complex unsolved\", \"Functional coupling of the coiled coil to caspase activation untested structurally\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked human BCAP31 loss-of-function to organelle morphology, establishing an in vivo requirement for ER-to-Golgi homeostasis distinct from the apoptotic/UPR axis.\",\n      \"evidence\": \"Patient-derived fibroblasts with LoF mutations, ER/Golgi immunofluorescence and UPR/cell-death marker assays\",\n      \"pmids\": [\"24011989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of Golgi disorganization undefined\", \"Which cargo defects drive the morphological phenotype unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a non-apoptotic metabolic role for BAP31 as an ER-mitochondria tether that delivers NDUFS4 to mitochondria via Tom40 to support complex I activity.\",\n      \"evidence\": \"Co-IP, NDUFS4 translocation, complex I activity and oxygen consumption assays with BAP31 knockdown\",\n      \"pmids\": [\"31206022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same contact site partitions apoptotic versus import functions unclear\", \"Generality to other imported subunits untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the atomic interface of the apoptotic tether, showing the BAP31 vDED engages the convex TPR surface of Fis1 with evidence for a Fis1 autoinhibitory arm.\",\n      \"evidence\": \"X-ray crystallography of Fis1 alone and the Fis1-Bap31_vDED co-complex\",\n      \"pmids\": [\"40770055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How procaspase-8 docks onto this interface not resolved\", \"Regulation of the proposed autoinhibitory arm in cells untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified post-translational control of BAP31 stability and activity through PINK1 phosphorylation at Ser142 and sirtuin 2 deacetylation at Lys158.\",\n      \"evidence\": \"Co-IP, site-directed S142A/S142E mutagenesis with ER-stress apoptosis readouts; SIRT2 knockdown and K158 acetylation mapping in liver injury models\",\n      \"pmids\": [\"41022756\", \"39887347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How these modifications alter BAP31 conformation or partner binding mechanistically unclear\", \"Crosstalk between phosphorylation and acetylation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BAP31 mechanistically partitions its many client and signaling roles — chaperone/export versus ERAD versus apoptotic scaffold versus mitochondrial tether — at a single ER-mitochondria platform remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of client recognition\", \"Rules determining export versus dislocation versus retention undefined\", \"Spatial/temporal switch between survival and death functions not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 15, 13]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [12, 14, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 20, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 16, 24]},\n      {\"term_id\": \"GO:0005789\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [20, 31]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [38]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 4, 7, 20, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [17, 12, 15]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 13, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 17]}\n    ],\n    \"complexes\": [\n      \"ARCosome (Fis1-BAP31-procaspase-8 platform)\",\n      \"BAP31-Bcl-2/Bcl-XL-procaspase-8 complex\",\n      \"Derlin-1 dislocation complex\",\n      \"BAP31-Tom40 ER-mitochondria tether\"\n    ],\n    \"partners\": [\n      \"BCL2L1\",\n      \"CASP8\",\n      \"FIS1\",\n      \"CDIP1\",\n      \"TOMM40\",\n      \"SEC61B\",\n      \"STX17\",\n      \"PINK1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}