{"gene":"BIRC3","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1997,"finding":"c-IAP-2 (BIRC3) directly binds and inhibits caspases-3 and -7 in vitro (but not caspase-8, -1, or -6). The BIR domain-containing region is sufficient for caspase inhibition. Recombinant c-IAP-2 also blocked caspase activation and pro-caspase-3 processing in cell-free cytochrome-c-activated extracts and in intact cells overexpressing the protein.","method":"In vitro binding assay, in vitro caspase activity assay (Ki estimation), cell-free caspase activation system, gene transfection overexpression in intact cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution with enzymatic assay and Ki determination, validated in cell-free system and intact cells; replicated across multiple orthogonal methods in a single rigorous study","pmids":["9384571"],"is_preprint":false},{"year":2005,"finding":"Although cIAP2 BIR2 and BIR3 domains bind caspases-7 and -9, they do NOT inhibit caspase activity because of critical substitutions in the caspase-inhibitory interaction sites present in XIAP. Substituting these residues with XIAP equivalents converts cIAP2 BIR domains into tight caspase inhibitors. Thus, cIAP2 maintains a caspase-binding scaffold but lacks direct caspase inhibitory activity.","method":"In vitro binding assay, in vitro caspase inhibition assay, site-directed mutagenesis to substitute XIAP residues","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis, single lab but multiple orthogonal methods contradicting prior positive claim","pmids":["16339151"],"is_preprint":false},{"year":2004,"finding":"cIAP2 (together with cIAP1) functions as an E3 ubiquitin ligase that directly ubiquitinates RIP1 in vitro, with the RING domain required for RIP1 degradation. Expression of cIAP2 decreased steady-state RIP1 levels in a proteasome-dependent manner.","method":"In vitro ubiquitination assay, ectopic expression, proteasome inhibitor treatment, domain deletion analysis (RING mutant)","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination reconstitution with RING domain mutagenesis, single lab but multiple methods","pmids":["15147886"],"is_preprint":false},{"year":2008,"finding":"cIAP2 functions as an E3 ubiquitin ligase that maintains constitutive K63-linked ubiquitination of RIP1 in cancer cells, promoting association of ubiquitinated RIP1 with the pro-survival kinase TAK1. When cIAP2 is degraded (by Smac mimetic AEG40730), RIP1 becomes deubiquitinated, binds caspase-8, and triggers apoptosis.","method":"E3 ligase assay (direct ubiquitination of RIP1), co-immunoprecipitation, Smac mimetic treatment, cancer cell line functional assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct ubiquitination assay plus reciprocal Co-IP with functional consequence; independently replicated in same period by other labs","pmids":["18570872"],"is_preprint":false},{"year":2008,"finding":"cIAP2 (redundantly with cIAP1) is required for RIP1 polyubiquitination and canonical NF-κB activation upon TNFα treatment. Both cIAPs are rapidly recruited to the TNFR1 signalosome upon TNFα stimulation. Combined loss of cIAP1 and cIAP2 blocks IKKβ phosphorylation and sensitizes cells to TNFα-mediated apoptosis.","method":"Combined genetic knockout and siRNA knockdown, co-immunoprecipitation with TNFR1 complex, RIP1 ubiquitination assay, IKKβ phosphorylation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with RNAi, reciprocal Co-IP, functional epistasis; replicated across multiple cell types including primary cells","pmids":["18697935"],"is_preprint":false},{"year":2008,"finding":"cIAP2 (redundantly with cIAP1) participates in a regulatory complex with TRAF2 and TRAF3 that targets NIK for constitutive proteasome-mediated degradation, thereby suppressing non-canonical NF-κB activation. TRAF3 recruits NIK and TRAF2 recruits cIAP1/2; inhibition of both cIAPs is required for non-canonical NF-κB activation.","method":"Genetic epistasis (double cIAP1/2 inhibition required), co-immunoprecipitation, NIK degradation assay, B-cell proliferation functional assay","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis with genetic and pharmacological inhibition, Co-IP of complex components, in vivo rescue experiments; independently confirmed by multiple labs","pmids":["18997794"],"is_preprint":false},{"year":2009,"finding":"cIAP2 (encoded by Birc3) is required as an E3 ubiquitin ligase for K63-linked ubiquitination of RIP2 and for NOD1/NOD2 innate immune signaling. Birc3-/- macrophages and colonocytes show severely attenuated cytokine/chemokine production in response to NOD agonists; in vivo, Birc3-/- mice fail to be protected by MDP (NOD2 agonist) from experimental colitis.","method":"Genetic knockout (Birc3-/- mice), RNAi knockdown, RIP2 ubiquitination assay, in vivo colitis model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with specific cellular and in vivo phenotype, E3 ligase activity assay for RIP2, validated both in vitro and in vivo","pmids":["19464198"],"is_preprint":false},{"year":2010,"finding":"Crystal structures of the TRAF2:cIAP2 binary complex and the TRAF1:TRAF2:cIAP2 ternary complex were solved. A TRAF2 trimer interacts with one cIAP2 molecule; two chains of the trimer contact cIAP2. Key interface residues were confirmed by mutagenesis. TRAF1:(TRAF2)2 heterotrimers bind cIAP2 more strongly than TRAF2 homotrimers, revealing a regulatory mechanism whereby TRAF1 upregulation modulates TRAF2-cIAP2 interaction.","method":"X-ray crystallography, mutagenesis of interface residues, solution binding assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures at atomic resolution with mutagenesis validation of interface; functionally informative about complex stoichiometry and regulation","pmids":["20385093"],"is_preprint":false},{"year":2011,"finding":"cIAP2 (with cIAP1 and TRAF2) directly interacts with caspase-1-containing inflammasome complexes and mediates K63-linked (non-degradative) polyubiquitination of caspase-1, which is required for efficient caspase-1 activation. Birc3-/- mice have impaired caspase-1 activation after inflammasome stimulation and are resistant to peritonitis.","method":"Co-immunoprecipitation, K63-linked ubiquitination assay of caspase-1, genetic knockout mice, in vivo peritonitis model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, KO mouse with defined phenotype, both in vitro and in vivo validation","pmids":["22195745"],"is_preprint":false},{"year":2006,"finding":"cIAP2 is an E3 ubiquitin ligase for BCL10 and targets it for proteasomal degradation, thereby inhibiting antigen receptor-mediated NF-κB activation and cytokine production. The cIAP2-MALT1 fusion oncoprotein (found in MALT lymphomas) lacks E3 activity, and BCL10 is stabilized in MALT lymphomas harboring this fusion.","method":"E3 ubiquitin ligase assay (in vitro ubiquitination of BCL10), co-immunoprecipitation, BCL10 degradation assay, NF-κB reporter assay, MALT lymphoma patient sample analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro ubiquitination assay with loss-of-E3-activity mutant, functional NF-κB assays, patient sample validation; single lab but multiple orthogonal methods","pmids":["16395405"],"is_preprint":false},{"year":2009,"finding":"cIAP2 regulates an event downstream of NEMO ubiquitination in genotoxic stress-induced NF-κB activation, distinct from and non-redundant with the roles of XIAP (upstream TAK1 activation) and cIAP1 (NEMO ubiquitination). This places cIAP2 as a component of the genotoxic NF-κB pathway downstream of NEMO.","method":"siRNA knockdown of individual IAPs, NF-κB luciferase reporter, epistasis analysis with NEMO ubiquitination assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis by RNAi with defined NF-κB readout, single lab, single method per step","pmids":["19223549"],"is_preprint":false},{"year":2011,"finding":"Loss of cIAP2 E3 ubiquitin ligase activity (via RING domain inactivation) is sufficient to stabilize NIK and activate non-canonical NF-κB signaling in vivo. Mice expressing E3-inactive cIAP2 accumulated abnormal B cells with elevated non-canonical NF-κB, gut-associated lymphoid hyperplasia, and other features resembling MALT lymphoma. Canonical NF-κB activation by cIAP2-MALT1 fusion depended on MALT1 paracaspase activity, while non-canonical activation required only loss of cIAP2 E3 activity.","method":"Knock-in mouse expressing E3-inactive cIAP2 mutant, B-cell phenotyping, NF-κB pathway activation assays, MALT1 paracaspase activity mutation","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in model with multiple orthogonal readouts (NIK stabilization, NF-κB activation, B-cell phenotype), validated with domain-specific mutants","pmids":["21048983"],"is_preprint":false},{"year":2011,"finding":"Smac mimetic-induced degradation of cIAP2 requires TRAF2 binding and depends on cIAP1 presence; degradation of cIAP2 also requires RING finger dimerization and E2 binding. Unlike cIAP1, cIAP2 degradation is not autonomous. The cIAP2-MALT1 oncofusion (lacking the RING) is resistant to Smac mimetic-induced degradation.","method":"Smac mimetic treatment, co-immunoprecipitation, RING domain mutants, cIAP1/2 double-knockout cell lines","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutants and KO cell lines, single lab, biochemical and cellular methods","pmids":["21331077"],"is_preprint":false},{"year":2013,"finding":"A cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex binds IKKε and mediates K63-linked polyubiquitination at lysine 30 and 401. This ubiquitination is required for IKKε kinase activity, IKKε-mediated NF-κB activation, and IKKε-induced malignant transformation in breast cancer cells.","method":"Co-immunoprecipitation, in vitro K63-ubiquitination assay, site-directed mutagenesis of ubiquitination sites, kinase activity assay, transformation assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct ubiquitination reconstitution, mutagenesis of acceptor sites, kinase activity assay with functional transformation readout; single lab but multiple orthogonal methods","pmids":["23453969"],"is_preprint":false},{"year":2004,"finding":"cIAP2 is a nuclear shuttling protein whose subcellular localization is regulated by CRM1-dependent nuclear export. TRAF2 binding retains cIAP2 in the cytoplasm, and TNFα treatment reduces this TRAF2-mediated cytoplasmic retention, potentially allowing nuclear translocation.","method":"Leptomycin B treatment, epitope-tagged protein localization, NES mutagenesis, TRAF2 co-expression experiments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with CRM1 inhibitor, NES mutagenesis, and TRAF2 co-expression; single lab","pmids":["15265700"],"is_preprint":false},{"year":2008,"finding":"cIAP2 mRNA is translated exclusively through a stress-modulated ribosome shunting mechanism that bypasses 62 upstream AUGs in the 2.78-kb 5' UTR. A conserved RNA folding domain (1,470–1,877 nt upstream) modulates shunting efficiency. Ribosome shunting efficiency is altered by cellular stress.","method":"In vitro translation assay, transfection of RNA reporters, selective mutation of shunt-donor sequences, comparison with internal ribosome entry site controls","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution and cell-based RNA reporter assays with mutagenesis; mechanistically distinct translational control mechanism established in single rigorous study","pmids":["18195037"],"is_preprint":false},{"year":2010,"finding":"Tristetraprolin (TTP) directly binds the 2nd AU-rich element (ARE) in the 3' UTR of cIAP2 mRNA and destabilizes cIAP2 mRNA by recruiting mRNA-decapping enzyme Dcp2 and 5'-3' exonuclease Xrn1, requiring flanking nucleotides beyond the core ARE sequence.","method":"RNA EMSA, mRNA stability assay (luciferase reporter), co-immunoprecipitation of TTP/Dcp2/Xrn1, mutagenesis of AREs","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding (EMSA), functional mRNA stability assay with ARE mutants, protein complex co-IP; single lab","pmids":["20691152"],"is_preprint":false},{"year":2011,"finding":"In glioma cells, NF-κB p65 directly transactivates cIAP2, as shown by ChIP at the BIRC3 promoter. p65-driven cIAP2 expression is required to maintain RIP1 polyubiquitination and thereby confer resistance to TNFα-mediated cell death.","method":"shRNA knockdown of p65, RT-PCR, chromatin immunoprecipitation (ChIP), RIP1 ubiquitination assay, TNFα cytotoxicity assay","journal":"Journal of neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct p65 binding to BIRC3 promoter, functional ubiquitination and cell death assays; single lab","pmids":["21279667"],"is_preprint":false},{"year":2011,"finding":"CBP histone acetyltransferase mediates NF-κB-dependent histone acetylation at an estrogen response element (ERE) in the BIRC3 promoter, enabling estrogen receptor (ER) recruitment to this ERE. NF-κB activation (acting through two response elements) is required for ER recruitment; CBP promotes both histone acetylation and ER binding at the BIRC3 promoter, leading to synergistic BIRC3 upregulation.","method":"ChIP, promoter deletion analysis, siRNA knockdown, luciferase reporter assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional reporter assays with defined promoter elements; single lab","pmids":["22083956"],"is_preprint":false},{"year":2011,"finding":"In HTLV-1-transformed lymphocytes, the viral oncoprotein Tax stimulates BIRC3 (HIAP-1/cIAP2) promoter activity ~60-fold primarily through NF-κB activation. RNAi-mediated suppression of cIAP2 in these cells causes dramatic reduction of cell growth, strong induction of apoptosis, and increased caspase-3/7 activity, establishing that Tax-mediated cIAP2 overexpression is required for survival of HTLV-1-transformed lymphocytes.","method":"Promoter-reporter transfection, RNAi via lentiviral transduction, apoptosis and caspase activity assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with defined apoptotic phenotype, promoter reporter assay; single lab","pmids":["16467195"],"is_preprint":false},{"year":2011,"finding":"cIAP2 inhibits the complete autocatalytic processing of caspase-3 from its p19 intermediate form to the fully mature p17 subunit during microglia activation, preventing full caspase-3 activation. This restrains caspase-3 activity and subcellular localization, allowing pro-inflammatory microglia activation rather than cell death. SMAC mimetic or cIAP2 siRNA reverses this effect.","method":"siRNA knockdown, SMAC mimetic (BV6), Western blot for caspase-3 subunits, immunofluorescence localization, LPS-mediated activation assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA + pharmacological inhibition with defined molecular readout (caspase-3 processing), single lab","pmids":["25501826"],"is_preprint":false},{"year":2012,"finding":"cIAP2 (together with cIAP1) limits RIP3 (and to a lesser extent RIP1) expression via post-transcriptional mechanisms, thereby inhibiting formation of the RIP1-RIP3 necroptotic complex (necrosome) in macrophages. Loss of cIAP function (via Smac mimetic or specific knockout) results in elevated macrophage necroptosis dependent on RIP1 kinase signaling and RIP3 expression.","method":"Smac mimetic treatment, specific cIAP knockout macrophages, RIP3 knockdown, RIP1 kinase inhibitor, protein level analysis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO macrophages with pharmacological and genetic epistasis; single lab, multiple methods","pmids":["22576661"],"is_preprint":false},{"year":2014,"finding":"cIAP2 deficiency in mice results in increased susceptibility to influenza A-induced mortality due to RIPK3-mediated programmed necrosis (necroptosis) of airway epithelial cells, not due to impaired antiviral immunity. Genetic deletion of Ripk3 or pharmacological inhibition of RIPK1, or deletion of death receptor agonists (FasL or TRAIL) from hematopoietic cells, rescued cIAP2-deficient mice from influenza lethality.","method":"Genetic knockout (Birc3-/- mice), Ripk3-/- and Ripk1 inhibitor epistasis, histopathology, viral replication assay, hematopoietic cell transfer","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with multiple genetic rescue experiments (Ripk3 KO, Ripk1 inhibitor, FasL/TRAIL deletion); defines precise pathway position","pmids":["24439895"],"is_preprint":false},{"year":2015,"finding":"USP11 is a deubiquitylase that directly stabilizes cIAP2 protein by removing ubiquitin chains, preventing Smac mimetic-induced cIAP2 degradation. High USP11 expression correlates with cIAP2 stability and resistance to Smac mimetic-induced apoptosis. TNFα/JNK pathway induces USP11 expression to maintain cIAP2 stability as an alternative survival pathway.","method":"Co-immunoprecipitation, ubiquitination assay, USP11 overexpression/knockdown, apoptosis assay, xenograft model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP of USP11-cIAP2, functional ubiquitination assay, KD with phenotype; single lab","pmids":["25613375"],"is_preprint":false},{"year":2011,"finding":"In BIRC3-disrupted CLL cells (via inactivating mutations or gene deletions removing the RING domain), constitutive non-canonical NF-κB signaling is activated, consistent with loss of cIAP2 E3 ligase-mediated NIK degradation. BIRC3 disruption associates specifically with fludarabine-refractory CLL.","method":"Biochemical analysis of non-canonical NF-κB activation (NIK stabilization, p52 processing) in primary CLL samples with BIRC3 mutations/deletions","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — biochemical pathway activation assay in primary patient samples correlating RING-domain loss with NIK/NF-κB activation; single lab, supports mechanistic model","pmids":["22308293"],"is_preprint":false},{"year":2012,"finding":"cIAP2 functions as an E3 ubiquitin ligase that promotes polyubiquitination and proteasome-mediated degradation of hepatitis B virus (HBV) polymerase. cIAP2 binds HBV polymerase, promotes its K48-linked ubiquitination, reduces encapsidation of HBV pregenomic RNA, and thereby inhibits HBV replication. An E3 ligase-deficient cIAP2 mutant loses this antiviral activity.","method":"Overexpression/knockdown of cIAP2, co-immunoprecipitation of cIAP2-polymerase, ubiquitination assay, proteasome inhibitor, HBV replication intermediates assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay with E3-dead mutant, functional viral replication assay; single lab","pmids":["21865390"],"is_preprint":false},{"year":2015,"finding":"NPD1 (neuroprotectin D1) induces nuclear translocation of cREL, which in turn mediates BIRC3 transcription. cREL-driven BIRC3 expression is required for NPD1-induced neural cell survival against oxidative stress; BIRC3 silencing prevents NPD1 survival induction. In vivo, brain NPD1 biosynthesis and neuronal BIRC3 abundance are increased by DHA after ischemic stroke.","method":"cREL nuclear translocation assay, BIRC3 promoter-reporter, siRNA knockdown of BIRC3, retinal pigment epithelial cell oxidative stress assay, in vivo stroke model with DHA treatment","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear translocation assay, promoter reporter, functional siRNA knockdown; single lab with in vitro and in vivo components","pmids":["25633199"],"is_preprint":false},{"year":2009,"finding":"An ARIA (apoptosis regulator through modulating IAP expression) protein promotes proteasomal degradation of cIAP2 in endothelial cells without affecting cIAP2 mRNA. ARIA interacts with 20S proteasome subunit alpha-7. ARIA knockdown increases cIAP2 protein and reduces endothelial apoptosis; simultaneous knockdown of both cIAP1 and cIAP2 abolishes the ARIA-knockdown anti-apoptotic effect.","method":"siRNA knockdown, protein stability assay, yeast two-hybrid (ARIA-proteasome interaction), overexpression, co-immunoprecipitation, in vivo angiogenesis models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double cIAP1/2 KD), proteasomal degradation assay, yeast two-hybrid for interaction; single lab","pmids":["19416853"],"is_preprint":false},{"year":2019,"finding":"The long 3' UTR of BIRC3 mRNA (upregulated in leukemia) is required for CXCR4-mediated B cell migration. The long 3' UTR enables formation of additional protein complexes not present when BIRC3 is encoded from short 3' UTR mRNA, including interactors regulating CXCR4 trafficking. RNA-binding proteins Staufen and HuR cooperatively bind the long 3' UTR to mediate this 3'-UTR-dependent complex formation.","method":"Mass spectrometry interactome of BIRC3 from long vs. short 3' UTR mRNA, CXCR4 trafficking assay, B cell migration assay, Staufen/HuR RIP assay","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry interactome with functional validation (migration, CXCR4 trafficking); single lab, multiple orthogonal methods","pmids":["30948266"],"is_preprint":false},{"year":2006,"finding":"Cell cycle-dependent expression of cIAP2 peaks at G2/M phase, mediated by a bipartite CDE/CHR element in the cIAP2 promoter. This G2/M-specific cIAP2 expression is enhanced by NF-κB but occurs independently of NF-κB. Selective downregulation of cIAP2 in nocodazole-arrested cells increases susceptibility to apoptosis, establishing a survival function specific to mitotic arrest.","method":"Cell cycle synchronization, promoter deletion/mutagenesis (CDE/CHR elements), siRNA knockdown, apoptosis assay in mitotically arrested cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis with cell-cycle synchronization, functional siRNA KD; single lab","pmids":["16813569"],"is_preprint":false},{"year":2017,"finding":"cIAP2 functions as an E3 ligase for MRE11 in bladder cancer cells following HDAC inhibition. cIAP2 is upregulated in response to HDAC inhibition, binds MRE11, promotes altered MRE11 ubiquitination and downregulation, and mediates radiosensitization. Overexpression of cIAP2 alone recapitulates the effects of HDAC inhibition on MRE11 levels.","method":"Co-immunoprecipitation (cIAP2-MRE11), ubiquitination assay, cIAP2 overexpression, radiosensitization assay, HDAC inhibitor treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional radiosensitization readout; single lab","pmids":["28363998"],"is_preprint":false},{"year":2016,"finding":"BIRC3 expression is upregulated in GBM in response to irradiation and temozolomide treatment through STAT3 and PI3K signaling pathways. BIRC3 upregulation promotes apoptosis evasion and therapeutic resistance; selective inhibition of BIRC3 reverses resistance.","method":"BIRC3 expression analysis after RT/TMZ, pathway inhibitor treatment (STAT3/PI3K), functional apoptosis assay in GBM cell lines and in vivo xenografts","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological pathway inhibitors with functional readout, single lab; STAT3/PI3K as upstream regulators established by inhibitor studies","pmids":["26888114"],"is_preprint":false},{"year":2019,"finding":"cIAP2 upregulation in CRC cells following Fusobacterium nucleatum infection is mediated via the TLR4/NF-κB pathway, and this cIAP2 upregulation confers resistance to 5-fluorouracil both in vitro and in vivo.","method":"Whole genome microarray, siRNA knockdown of BIRC3, in vitro and in vivo 5-FU sensitivity assay, NF-κB pathway inhibition","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with functional chemosensitivity assay in vitro and xenograft; single lab, TLR4/NF-κB epistasis by pathway inhibition","pmids":["30630498"],"is_preprint":false},{"year":2019,"finding":"cIAP2 ubiquitinates RIPK1 to maintain NF-κB signaling and cell survival. Combined in vivo deletion of cIap2 from cIap1-deficient adult mice causes rapid inflammation and aberrant caspase-8-dependent cell death in intestine and liver; Casp8 + Ripk3 double deletion prevents this cell death and partially reduces inflammation. Residual inflammation in cIAP1/2-deficient mice is reduced by NIK inhibition.","method":"Conditional double-KO mouse (inducible cIap2 deletion in cIap1-KO background), Casp8/Ripk3/Mlkl genetic deletion epistasis, NIK inhibitor, histopathology, cleaved caspase immunoblot","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with multiple KO combinations defining caspase-8-dependent cell death as primary cIAP1/2 target; rigorous in vivo design","pmids":["31141691"],"is_preprint":false},{"year":2022,"finding":"USP35 is a deubiquitylase that directly interacts with and stabilizes BIRC3 by removing K48-linked polyubiquitin chains, preventing proteasomal degradation. USP35 overexpression increases BIRC3 abundance and confers resistance to cisplatin-induced apoptosis in NSCLC cells; USP35 knockdown reduces BIRC3 and sensitizes cells to cisplatin.","method":"Co-immunoprecipitation, ubiquitination assay (K48-specific), USP35 overexpression/knockdown, BIRC3 protein stability assay, apoptosis assay","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP and ubiquitination assay with functional apoptosis readout; single lab","pmids":["35022505"],"is_preprint":false},{"year":2016,"finding":"Pellino-1 E3 ubiquitin ligase directly interacts with cIAP2 and stabilizes it through Lys63-linked polyubiquitination, conferring chemoresistance to cisplatin and paclitaxel in lung cancer cells. Pellino-1-mediated chemoresistance is dependent on cIAP2 induction.","method":"Co-immunoprecipitation, K63-ubiquitination assay, Pellino-1 overexpression/knockdown, chemosensitivity assay, epistasis with cIAP2 knockdown","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP and ubiquitination assay with epistasis (cIAP2 KD rescues Pellino-1 effect); single lab","pmids":["27248820"],"is_preprint":false},{"year":2012,"finding":"cIAP2 knockdown in mammary epithelial cells activates MDM2 through increased SUMOylation and IKKα/β-dependent phosphorylation, causing p53 degradation. cIAP2 prevents IKKα/β-mediated MDM2 activation; concomitant IKKα/β inhibition rescues p53 levels after cIAP2 knockdown. cIAP2 knockdown disrupts the PIAS1-IKKα interaction required to prevent MDM2 SUMOylation.","method":"siRNA knockdown, MDM2 SUMOylation assay, IKKα/β inhibition, immunoprecipitation of PIAS1-IKKα complex, p53 level rescue by Nutlin-3a","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (SUMOylation, phosphorylation, Co-IP) with genetic epistasis; single lab","pmids":["23032264"],"is_preprint":false},{"year":2015,"finding":"BIRC3 mutations that remove the RING domain (abolishing E3 ubiquitin ligase activity) confer direct oncogenic/transforming potential in a wide range of epithelial tumor cell lines. This transforming function is largely independent of canonical NF-κB activation. NIK is an important but not exclusive mediator of BIRC3-mutant-driven carcinogenesis, acting through pathways other than NF-κB.","method":"Transformation assay (focus formation, anchorage-independent growth), RING domain mutants, NF-κB reporter, NIK knockdown epistasis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transformation assay with multiple RING mutants and NIK epistasis; single lab, functional readouts","pmids":["26094954"],"is_preprint":false},{"year":2020,"finding":"H. pylori CagA protein induces resistance to caspase-3-mediated apoptosis in gastric epithelial cells via Brd4-dependent synthesis of a BIRC3 enhancer RNA (eRNA), which drives BIRC3 mRNA and cIAP2 protein upregulation. Depletion of BIRC3 eRNA or inhibition of Brd4 reverses H. pylori-induced cIAP2 induction and apoptosis resistance. CagA-deficient H. pylori mutant fails to activate BIRC3 eRNA synthesis.","method":"siRNA knockdown of BIRC3 eRNA and BIRC3, Brd4 inhibitor, CagA-deficient bacterial mutant, caspase-3 activation assay, ChIP for Brd4 at BIRC3 enhancer","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — eRNA knockdown with functional apoptosis readout, Brd4 ChIP, genetic bacterial mutant; single lab","pmids":["32820150"],"is_preprint":false},{"year":2023,"finding":"During anastasis (recovery from executioner caspase activation), colorectal cancer cells upregulate cIAP2 and activate NF-κB. This elevated cIAP2/NF-κB signaling persists in anastatic cells and is required both for initial survival of caspase activation and for subsequent enhanced migration, metastasis, and chemoresistance.","method":"Lineage-tracing system to isolate anastatic cells, cIAP2 knockdown, NF-κB inhibition, caspase activation reporter, migration and chemoresistance assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lineage tracing with defined molecular mechanism (cIAP2/NF-κB), functional KD epistasis; single lab","pmids":["37391410"],"is_preprint":false}],"current_model":"BIRC3 (cIAP2) is a RING-domain E3 ubiquitin ligase that suppresses apoptosis and inflammation primarily by ubiquitinating key signaling substrates: it maintains K63-linked polyubiquitination of RIP1/RIPK1 (promoting canonical NF-κB survival signaling and preventing caspase-8-dependent cell death), mediates K48-linked ubiquitination of NIK to drive its proteasomal degradation and thus suppress non-canonical NF-κB, ubiquitinates RIP2 for NOD1/2 innate immune signaling, mediates K63-linked ubiquitination of caspase-1 for inflammasome activation, and acts as an E3 for additional substrates including BCL10, IKKε, MRE11, and HBV polymerase; its subcellular localization is regulated by CRM1-dependent nuclear export and TRAF2-mediated cytoplasmic retention; its mRNA undergoes stress-modulated ribosome shunting for translation and is destabilized by TTP binding to a 3' UTR ARE; and deubiquitylases USP11 and USP35 stabilize the protein by removing ubiquitin chains, while loss of its RING-domain E3 activity (by mutation or the cIAP2-MALT1 oncofusion) constitutively activates non-canonical NF-κB and can confer direct oncogenic transformation."},"narrative":{"mechanistic_narrative":"BIRC3 (cIAP2) is a RING-domain E3 ubiquitin ligase that governs the balance between cell survival, apoptosis, necroptosis, and inflammatory signaling by ubiquitinating key signaling substrates [PMID:18570872, PMID:18997794, PMID:31141691]. Although its BIR domains bind caspases-3, -7, and -9, critical substitutions relative to XIAP render it a caspase-binding scaffold rather than a direct caspase inhibitor [PMID:16339151]. Its dominant survival function is the E3 ligase-dependent K63-linked ubiquitination of RIP1/RIPK1, which it performs redundantly with cIAP1 after recruitment to the TNFR1 signalosome; this maintains canonical NF-κB survival signaling and prevents RIP1 from binding caspase-8 to trigger cell death [PMID:18570872, PMID:18697935, PMID:31141691]. In parallel, cIAP2 works with TRAF2/TRAF3 to mediate constitutive proteasomal degradation of NIK, suppressing non-canonical NF-κB; loss of its RING-domain E3 activity stabilizes NIK and constitutively activates this pathway, driving B-cell hyperplasia and direct oncogenic transformation [PMID:18997794, PMID:21048983, PMID:26094954]. Beyond these axes it ubiquitinates BCL10 to restrain antigen-receptor NF-κB signaling [PMID:16395405], RIP2 for NOD1/2 innate immunity [PMID:19464198], caspase-1 for inflammasome activation [PMID:22195745], and IKKε to support its kinase activity and transforming function [PMID:23453969]. By limiting RIP3/RIP1 necrosome formation, cIAP2 also restrains RIPK3-dependent necroptosis, protecting against influenza A-induced epithelial death [PMID:22576661, PMID:24439895]. The crystal structure of the TRAF2:cIAP2 complex shows a TRAF2 trimer engaging one cIAP2 molecule, with TRAF1 incorporation strengthening the interaction [PMID:20385093]. Its abundance is set by deubiquitylases USP11 and USP35, which remove ubiquitin chains to stabilize the protein and confer therapeutic resistance [PMID:25613375, PMID:35022505]. BIRC3 is transcriptionally driven by NF-κB family members [PMID:21279667, PMID:22083956], and its inactivating RING-domain mutations are associated with fludarabine-refractory chronic lymphocytic leukemia [PMID:22308293].","teleology":[{"year":1997,"claim":"Established the first biochemical activity for cIAP2 by testing whether it directly inhibits caspases, the central question for an 'IAP' family member.","evidence":"In vitro binding/caspase activity assays, cell-free cytochrome-c extracts, and overexpression in cells","pmids":["9384571"],"confidence":"High","gaps":["Did not assess physiological stoichiometry or endogenous relevance","Conflicted with later structural analysis of caspase-binding sites"]},{"year":2005,"claim":"Revised the caspase-inhibitor model by showing cIAP2 BIR domains bind but do not inhibit caspases, reframing it as a scaffold rather than an effector inhibitor.","evidence":"In vitro binding/inhibition assays with site-directed mutagenesis swapping in XIAP residues","pmids":["16339151"],"confidence":"High","gaps":["Did not establish what the caspase-binding scaffold does in cells","Functional consequence of caspase binding without inhibition unresolved"]},{"year":2004,"claim":"Identified cIAP2 as an E3 ubiquitin ligase acting on RIP1, shifting the field from apoptosis inhibition to ubiquitin-mediated signaling control.","evidence":"In vitro ubiquitination assay, ectopic expression with proteasome inhibitor, and RING-domain deletion; separately, CRM1-dependent nuclear export and TRAF2 cytoplasmic retention defined","pmids":["15147886","15265700"],"confidence":"High","gaps":["Initial study emphasized degradative RIP1 turnover rather than non-degradative chains","Functional role of nuclear pool of cIAP2 not defined"]},{"year":2006,"claim":"Extended E3 substrate range to BCL10 and tied loss of E3 activity to the cIAP2-MALT1 oncofusion, providing the first link between E3 inactivation and lymphomagenesis.","evidence":"In vitro ubiquitination of BCL10, NF-κB reporter, and MALT lymphoma patient sample analysis","pmids":["16395405"],"confidence":"High","gaps":["Mechanism by which the fusion drives oncogenesis beyond BCL10 stabilization unresolved"]},{"year":2008,"claim":"Defined the dual NF-κB roles: cIAP2 maintains K63-ubiquitinated RIP1 for canonical survival signaling at TNFR1, and degrades NIK with TRAF2/3 to suppress non-canonical signaling.","evidence":"Genetic KO/RNAi, TNFR1-complex Co-IP, RIP1/IKKβ assays, NIK degradation, and Smac mimetic functional assays","pmids":["18570872","18697935","18997794"],"confidence":"High","gaps":["Redundancy with cIAP1 complicates assigning cIAP2-specific contributions","Chain-type switching between K63 and K48 on shared substrates not fully resolved"]},{"year":2009,"claim":"Demonstrated cIAP2 is required for RIP2 K63-ubiquitination and NOD1/2 innate immune signaling in vivo, broadening its role to pattern-recognition immunity.","evidence":"Birc3-/- mice, RNAi, RIP2 ubiquitination assay, and in vivo MDP/colitis model; separately, NEMO-downstream genotoxic NF-κB role by RNAi epistasis","pmids":["19464198","19223549"],"confidence":"High","gaps":["Mechanism distinguishing cIAP2 from cIAP1/XIAP in genotoxic pathway remains correlative"]},{"year":2010,"claim":"Provided atomic-resolution insight into how cIAP2 is recruited to signaling complexes via TRAF2, and how TRAF1 regulates the interaction.","evidence":"X-ray crystallography of TRAF2:cIAP2 and TRAF1:TRAF2:cIAP2 complexes with interface mutagenesis","pmids":["20385093"],"confidence":"High","gaps":["Structures do not capture catalytically engaged RING/E2 state","Dynamics of recruitment to active signalosomes not visualized"]},{"year":2011,"claim":"Showed loss of cIAP2 E3 activity alone stabilizes NIK and drives non-canonical NF-κB and MALT-lymphoma-like B-cell pathology in vivo, and linked RING-domain disruption to fludarabine-refractory CLL.","evidence":"E3-inactive knock-in mice, B-cell phenotyping, and biochemical analysis of NIK/p52 in primary CLL samples; also caspase-1 inflammasome ubiquitination and translational control studies","pmids":["21048983","22308293","22195745","18195037","16813569"],"confidence":"High","gaps":["How loss of E3 activity selectively activates non-canonical over canonical signaling not fully mechanistic","Cell-cycle-coupled survival role (G2/M) not integrated with signaling roles"]},{"year":2012,"claim":"Established cIAP2 as a brake on RIPK3-dependent necroptosis by post-transcriptionally limiting necrosome components, and expanded substrate range to viral and tumor-suppressor pathways.","evidence":"KO macrophages with Smac mimetic/RIP1 inhibitor epistasis; HBV polymerase ubiquitination assays; MDM2/p53 SUMOylation biochemistry","pmids":["22576661","21865390","23032264"],"confidence":"Medium","gaps":["Mechanism of post-transcriptional RIP3 control undefined","MDM2/p53 link rests on RNAi in one system"]},{"year":2014,"claim":"Resolved the in vivo physiological consequence of necroptosis restraint, showing cIAP2 protects airway epithelium from RIPK3-mediated death during influenza.","evidence":"Birc3-/- mice with Ripk3 KO, RIPK1 inhibitor, and FasL/TRAIL deletion rescue","pmids":["24439895"],"confidence":"High","gaps":["Whether protection is purely E3-dependent not directly tested"]},{"year":2017,"claim":"Demonstrated cIAP2 abundance is post-translationally tuned by deubiquitylases and an opposing E3, and expanded substrates to DNA-repair factor MRE11 with therapeutic relevance.","evidence":"USP11 Co-IP/ubiquitination with xenograft; ARIA-proteasome degradation; Pellino-1 K63 stabilization; cIAP2-MRE11 Co-IP and radiosensitization","pmids":["25613375","19416853","27248820","28363998"],"confidence":"Medium","gaps":["Hierarchy among competing stabilizing/destabilizing regulators in vivo unknown","MRE11 ubiquitination chain-type and site not fully defined"]},{"year":2019,"claim":"Defined how cIAP1/2 loss together triggers caspase-8-dependent intestinal/hepatic pathology in vivo, and uncovered a 3'-UTR-dependent moonlighting role in CXCR4-mediated B-cell migration.","evidence":"Inducible cIap1/cIap2 double-KO mice with Casp8/Ripk3 epistasis and NIK inhibition; BIRC3 long-3'UTR interactome with Staufen/HuR and migration assays","pmids":["31141691","30948266"],"confidence":"High","gaps":["3'-UTR-dependent complex composition only partially characterized","Relationship between protein E3 function and mRNA-scaffolding role unclear"]},{"year":2022,"claim":"Reinforced deubiquitylase-mediated stabilization as a resistance mechanism, with USP35 removing K48 chains to protect cIAP2 and confer cisplatin resistance.","evidence":"Co-IP, K48-specific ubiquitination assay, and apoptosis assays in NSCLC cells","pmids":["35022505"],"confidence":"Medium","gaps":["Whether USP11 and USP35 act redundantly or context-specifically not tested"]},{"year":2023,"claim":"Showed elevated cIAP2/NF-κB signaling enables anastatic recovery from executioner caspase activation, conferring metastatic and chemoresistant properties.","evidence":"Lineage-tracing isolation of anastatic CRC cells with cIAP2 knockdown and NF-κB inhibition","pmids":["37391410"],"confidence":"Medium","gaps":["Direct substrate driving anastatic survival not identified","Single cancer-cell system"]},{"year":null,"claim":"How the diverse upstream regulators (transcriptional, translational, and stability-based) integrate to set cIAP2 levels at specific subcellular sites, and how a single RING ligase selects among K63 versus K48 chains on its many substrates in vivo, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for chain-type selectivity across substrates","Functional significance of nuclear cIAP2 pool undefined","cIAP1/cIAP2 division of labor incompletely resolved in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2,3,6,9,13,25,30]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,6,8,9,13,25,30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,11]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[28]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,5,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,21,22,33]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,24,37]}],"complexes":["TRAF2:cIAP2 complex","TRAF1:TRAF2:cIAP2 complex","TNFR1 signalosome"],"partners":["TRAF2","TRAF3","RIPK1","NIK","BCL10","IKBKE","USP11","USP35"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13489","full_name":"Baculoviral IAP repeat-containing protein 3","aliases":["Apoptosis inhibitor 2","API2","Cellular inhibitor of apoptosis 2","C-IAP2","IAP homolog C","Inhibitor of apoptosis protein 1","hIAP-1","hIAP1","RING finger protein 49","RING-type E3 ubiquitin transferase BIRC3","TNFR2-TRAF-signaling complex protein 1"],"length_aa":604,"mass_kda":68.4,"function":"Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, IKBKE, TRAF1, and BCL10. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13489/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BIRC3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BIRC3","total_profiled":1310},"omim":[{"mim_id":"616701","title":"COMM DOMAIN-CONTAINING PROTEIN 4; COMMD4","url":"https://www.omim.org/entry/616701"},{"mim_id":"612377","title":"COMM DOMAIN-CONTAINING PROTEIN 6; COMMD6","url":"https://www.omim.org/entry/612377"},{"mim_id":"607238","title":"COMM DOMAIN-CONTAINING PROTEIN 1; COMMD1","url":"https://www.omim.org/entry/607238"},{"mim_id":"606441","title":"HTRA SERINE PEPTIDASE 2; HTRA2","url":"https://www.omim.org/entry/606441"},{"mim_id":"605737","title":"BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 7; BIRC7","url":"https://www.omim.org/entry/605737"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":83.8},{"tissue":"lymphoid tissue","ntpm":132.2}],"url":"https://www.proteinatlas.org/search/BIRC3"},"hgnc":{"alias_symbol":["cIAP2","hiap-1","MIHC","RNF49","MALT2","c-IAP2"],"prev_symbol":["API2"]},"alphafold":{"accession":"Q13489","domains":[{"cath_id":"1.10.1170.10","chopping":"30-100","consensus_level":"high","plddt":82.7551,"start":30,"end":100},{"cath_id":"1.10.1170.10","chopping":"165-243","consensus_level":"high","plddt":87.2728,"start":165,"end":243},{"cath_id":"1.10.1170.10","chopping":"251-340","consensus_level":"medium","plddt":84.3211,"start":251,"end":340},{"cath_id":"1.10.8.10","chopping":"376-437","consensus_level":"medium","plddt":79.6442,"start":376,"end":437},{"cath_id":"1.10.533.10","chopping":"440-537","consensus_level":"medium","plddt":90.5274,"start":440,"end":537},{"cath_id":"3.30.40.10","chopping":"540-604","consensus_level":"medium","plddt":76.1869,"start":540,"end":604}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13489","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13489-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13489-F1-predicted_aligned_error_v6.png","plddt_mean":74.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BIRC3","jax_strain_url":"https://www.jax.org/strain/search?query=BIRC3"},"sequence":{"accession":"Q13489","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13489.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13489/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13489"}},"corpus_meta":[{"pmid":"9384571","id":"PMC_9384571","title":"The 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The BIR domain-containing region is sufficient for caspase inhibition. Recombinant c-IAP-2 also blocked caspase activation and pro-caspase-3 processing in cell-free cytochrome-c-activated extracts and in intact cells overexpressing the protein.\",\n      \"method\": \"In vitro binding assay, in vitro caspase activity assay (Ki estimation), cell-free caspase activation system, gene transfection overexpression in intact cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution with enzymatic assay and Ki determination, validated in cell-free system and intact cells; replicated across multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"9384571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Although cIAP2 BIR2 and BIR3 domains bind caspases-7 and -9, they do NOT inhibit caspase activity because of critical substitutions in the caspase-inhibitory interaction sites present in XIAP. Substituting these residues with XIAP equivalents converts cIAP2 BIR domains into tight caspase inhibitors. Thus, cIAP2 maintains a caspase-binding scaffold but lacks direct caspase inhibitory activity.\",\n      \"method\": \"In vitro binding assay, in vitro caspase inhibition assay, site-directed mutagenesis to substitute XIAP residues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis, single lab but multiple orthogonal methods contradicting prior positive claim\",\n      \"pmids\": [\"16339151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"cIAP2 (together with cIAP1) functions as an E3 ubiquitin ligase that directly ubiquitinates RIP1 in vitro, with the RING domain required for RIP1 degradation. Expression of cIAP2 decreased steady-state RIP1 levels in a proteasome-dependent manner.\",\n      \"method\": \"In vitro ubiquitination assay, ectopic expression, proteasome inhibitor treatment, domain deletion analysis (RING mutant)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination reconstitution with RING domain mutagenesis, single lab but multiple methods\",\n      \"pmids\": [\"15147886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"cIAP2 functions as an E3 ubiquitin ligase that maintains constitutive K63-linked ubiquitination of RIP1 in cancer cells, promoting association of ubiquitinated RIP1 with the pro-survival kinase TAK1. When cIAP2 is degraded (by Smac mimetic AEG40730), RIP1 becomes deubiquitinated, binds caspase-8, and triggers apoptosis.\",\n      \"method\": \"E3 ligase assay (direct ubiquitination of RIP1), co-immunoprecipitation, Smac mimetic treatment, cancer cell line functional assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct ubiquitination assay plus reciprocal Co-IP with functional consequence; independently replicated in same period by other labs\",\n      \"pmids\": [\"18570872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"cIAP2 (redundantly with cIAP1) is required for RIP1 polyubiquitination and canonical NF-κB activation upon TNFα treatment. Both cIAPs are rapidly recruited to the TNFR1 signalosome upon TNFα stimulation. Combined loss of cIAP1 and cIAP2 blocks IKKβ phosphorylation and sensitizes cells to TNFα-mediated apoptosis.\",\n      \"method\": \"Combined genetic knockout and siRNA knockdown, co-immunoprecipitation with TNFR1 complex, RIP1 ubiquitination assay, IKKβ phosphorylation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with RNAi, reciprocal Co-IP, functional epistasis; replicated across multiple cell types including primary cells\",\n      \"pmids\": [\"18697935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"cIAP2 (redundantly with cIAP1) participates in a regulatory complex with TRAF2 and TRAF3 that targets NIK for constitutive proteasome-mediated degradation, thereby suppressing non-canonical NF-κB activation. TRAF3 recruits NIK and TRAF2 recruits cIAP1/2; inhibition of both cIAPs is required for non-canonical NF-κB activation.\",\n      \"method\": \"Genetic epistasis (double cIAP1/2 inhibition required), co-immunoprecipitation, NIK degradation assay, B-cell proliferation functional assay\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis with genetic and pharmacological inhibition, Co-IP of complex components, in vivo rescue experiments; independently confirmed by multiple labs\",\n      \"pmids\": [\"18997794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"cIAP2 (encoded by Birc3) is required as an E3 ubiquitin ligase for K63-linked ubiquitination of RIP2 and for NOD1/NOD2 innate immune signaling. Birc3-/- macrophages and colonocytes show severely attenuated cytokine/chemokine production in response to NOD agonists; in vivo, Birc3-/- mice fail to be protected by MDP (NOD2 agonist) from experimental colitis.\",\n      \"method\": \"Genetic knockout (Birc3-/- mice), RNAi knockdown, RIP2 ubiquitination assay, in vivo colitis model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with specific cellular and in vivo phenotype, E3 ligase activity assay for RIP2, validated both in vitro and in vivo\",\n      \"pmids\": [\"19464198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structures of the TRAF2:cIAP2 binary complex and the TRAF1:TRAF2:cIAP2 ternary complex were solved. A TRAF2 trimer interacts with one cIAP2 molecule; two chains of the trimer contact cIAP2. Key interface residues were confirmed by mutagenesis. TRAF1:(TRAF2)2 heterotrimers bind cIAP2 more strongly than TRAF2 homotrimers, revealing a regulatory mechanism whereby TRAF1 upregulation modulates TRAF2-cIAP2 interaction.\",\n      \"method\": \"X-ray crystallography, mutagenesis of interface residues, solution binding assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures at atomic resolution with mutagenesis validation of interface; functionally informative about complex stoichiometry and regulation\",\n      \"pmids\": [\"20385093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"cIAP2 (with cIAP1 and TRAF2) directly interacts with caspase-1-containing inflammasome complexes and mediates K63-linked (non-degradative) polyubiquitination of caspase-1, which is required for efficient caspase-1 activation. Birc3-/- mice have impaired caspase-1 activation after inflammasome stimulation and are resistant to peritonitis.\",\n      \"method\": \"Co-immunoprecipitation, K63-linked ubiquitination assay of caspase-1, genetic knockout mice, in vivo peritonitis model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, KO mouse with defined phenotype, both in vitro and in vivo validation\",\n      \"pmids\": [\"22195745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"cIAP2 is an E3 ubiquitin ligase for BCL10 and targets it for proteasomal degradation, thereby inhibiting antigen receptor-mediated NF-κB activation and cytokine production. The cIAP2-MALT1 fusion oncoprotein (found in MALT lymphomas) lacks E3 activity, and BCL10 is stabilized in MALT lymphomas harboring this fusion.\",\n      \"method\": \"E3 ubiquitin ligase assay (in vitro ubiquitination of BCL10), co-immunoprecipitation, BCL10 degradation assay, NF-κB reporter assay, MALT lymphoma patient sample analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro ubiquitination assay with loss-of-E3-activity mutant, functional NF-κB assays, patient sample validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16395405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"cIAP2 regulates an event downstream of NEMO ubiquitination in genotoxic stress-induced NF-κB activation, distinct from and non-redundant with the roles of XIAP (upstream TAK1 activation) and cIAP1 (NEMO ubiquitination). This places cIAP2 as a component of the genotoxic NF-κB pathway downstream of NEMO.\",\n      \"method\": \"siRNA knockdown of individual IAPs, NF-κB luciferase reporter, epistasis analysis with NEMO ubiquitination assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis by RNAi with defined NF-κB readout, single lab, single method per step\",\n      \"pmids\": [\"19223549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of cIAP2 E3 ubiquitin ligase activity (via RING domain inactivation) is sufficient to stabilize NIK and activate non-canonical NF-κB signaling in vivo. Mice expressing E3-inactive cIAP2 accumulated abnormal B cells with elevated non-canonical NF-κB, gut-associated lymphoid hyperplasia, and other features resembling MALT lymphoma. Canonical NF-κB activation by cIAP2-MALT1 fusion depended on MALT1 paracaspase activity, while non-canonical activation required only loss of cIAP2 E3 activity.\",\n      \"method\": \"Knock-in mouse expressing E3-inactive cIAP2 mutant, B-cell phenotyping, NF-κB pathway activation assays, MALT1 paracaspase activity mutation\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in model with multiple orthogonal readouts (NIK stabilization, NF-κB activation, B-cell phenotype), validated with domain-specific mutants\",\n      \"pmids\": [\"21048983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Smac mimetic-induced degradation of cIAP2 requires TRAF2 binding and depends on cIAP1 presence; degradation of cIAP2 also requires RING finger dimerization and E2 binding. Unlike cIAP1, cIAP2 degradation is not autonomous. The cIAP2-MALT1 oncofusion (lacking the RING) is resistant to Smac mimetic-induced degradation.\",\n      \"method\": \"Smac mimetic treatment, co-immunoprecipitation, RING domain mutants, cIAP1/2 double-knockout cell lines\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutants and KO cell lines, single lab, biochemical and cellular methods\",\n      \"pmids\": [\"21331077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex binds IKKε and mediates K63-linked polyubiquitination at lysine 30 and 401. This ubiquitination is required for IKKε kinase activity, IKKε-mediated NF-κB activation, and IKKε-induced malignant transformation in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro K63-ubiquitination assay, site-directed mutagenesis of ubiquitination sites, kinase activity assay, transformation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct ubiquitination reconstitution, mutagenesis of acceptor sites, kinase activity assay with functional transformation readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23453969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"cIAP2 is a nuclear shuttling protein whose subcellular localization is regulated by CRM1-dependent nuclear export. TRAF2 binding retains cIAP2 in the cytoplasm, and TNFα treatment reduces this TRAF2-mediated cytoplasmic retention, potentially allowing nuclear translocation.\",\n      \"method\": \"Leptomycin B treatment, epitope-tagged protein localization, NES mutagenesis, TRAF2 co-expression experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with CRM1 inhibitor, NES mutagenesis, and TRAF2 co-expression; single lab\",\n      \"pmids\": [\"15265700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"cIAP2 mRNA is translated exclusively through a stress-modulated ribosome shunting mechanism that bypasses 62 upstream AUGs in the 2.78-kb 5' UTR. A conserved RNA folding domain (1,470–1,877 nt upstream) modulates shunting efficiency. Ribosome shunting efficiency is altered by cellular stress.\",\n      \"method\": \"In vitro translation assay, transfection of RNA reporters, selective mutation of shunt-donor sequences, comparison with internal ribosome entry site controls\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution and cell-based RNA reporter assays with mutagenesis; mechanistically distinct translational control mechanism established in single rigorous study\",\n      \"pmids\": [\"18195037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tristetraprolin (TTP) directly binds the 2nd AU-rich element (ARE) in the 3' UTR of cIAP2 mRNA and destabilizes cIAP2 mRNA by recruiting mRNA-decapping enzyme Dcp2 and 5'-3' exonuclease Xrn1, requiring flanking nucleotides beyond the core ARE sequence.\",\n      \"method\": \"RNA EMSA, mRNA stability assay (luciferase reporter), co-immunoprecipitation of TTP/Dcp2/Xrn1, mutagenesis of AREs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding (EMSA), functional mRNA stability assay with ARE mutants, protein complex co-IP; single lab\",\n      \"pmids\": [\"20691152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In glioma cells, NF-κB p65 directly transactivates cIAP2, as shown by ChIP at the BIRC3 promoter. p65-driven cIAP2 expression is required to maintain RIP1 polyubiquitination and thereby confer resistance to TNFα-mediated cell death.\",\n      \"method\": \"shRNA knockdown of p65, RT-PCR, chromatin immunoprecipitation (ChIP), RIP1 ubiquitination assay, TNFα cytotoxicity assay\",\n      \"journal\": \"Journal of neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct p65 binding to BIRC3 promoter, functional ubiquitination and cell death assays; single lab\",\n      \"pmids\": [\"21279667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CBP histone acetyltransferase mediates NF-κB-dependent histone acetylation at an estrogen response element (ERE) in the BIRC3 promoter, enabling estrogen receptor (ER) recruitment to this ERE. NF-κB activation (acting through two response elements) is required for ER recruitment; CBP promotes both histone acetylation and ER binding at the BIRC3 promoter, leading to synergistic BIRC3 upregulation.\",\n      \"method\": \"ChIP, promoter deletion analysis, siRNA knockdown, luciferase reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional reporter assays with defined promoter elements; single lab\",\n      \"pmids\": [\"22083956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In HTLV-1-transformed lymphocytes, the viral oncoprotein Tax stimulates BIRC3 (HIAP-1/cIAP2) promoter activity ~60-fold primarily through NF-κB activation. RNAi-mediated suppression of cIAP2 in these cells causes dramatic reduction of cell growth, strong induction of apoptosis, and increased caspase-3/7 activity, establishing that Tax-mediated cIAP2 overexpression is required for survival of HTLV-1-transformed lymphocytes.\",\n      \"method\": \"Promoter-reporter transfection, RNAi via lentiviral transduction, apoptosis and caspase activity assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with defined apoptotic phenotype, promoter reporter assay; single lab\",\n      \"pmids\": [\"16467195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"cIAP2 inhibits the complete autocatalytic processing of caspase-3 from its p19 intermediate form to the fully mature p17 subunit during microglia activation, preventing full caspase-3 activation. This restrains caspase-3 activity and subcellular localization, allowing pro-inflammatory microglia activation rather than cell death. SMAC mimetic or cIAP2 siRNA reverses this effect.\",\n      \"method\": \"siRNA knockdown, SMAC mimetic (BV6), Western blot for caspase-3 subunits, immunofluorescence localization, LPS-mediated activation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA + pharmacological inhibition with defined molecular readout (caspase-3 processing), single lab\",\n      \"pmids\": [\"25501826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"cIAP2 (together with cIAP1) limits RIP3 (and to a lesser extent RIP1) expression via post-transcriptional mechanisms, thereby inhibiting formation of the RIP1-RIP3 necroptotic complex (necrosome) in macrophages. Loss of cIAP function (via Smac mimetic or specific knockout) results in elevated macrophage necroptosis dependent on RIP1 kinase signaling and RIP3 expression.\",\n      \"method\": \"Smac mimetic treatment, specific cIAP knockout macrophages, RIP3 knockdown, RIP1 kinase inhibitor, protein level analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages with pharmacological and genetic epistasis; single lab, multiple methods\",\n      \"pmids\": [\"22576661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"cIAP2 deficiency in mice results in increased susceptibility to influenza A-induced mortality due to RIPK3-mediated programmed necrosis (necroptosis) of airway epithelial cells, not due to impaired antiviral immunity. Genetic deletion of Ripk3 or pharmacological inhibition of RIPK1, or deletion of death receptor agonists (FasL or TRAIL) from hematopoietic cells, rescued cIAP2-deficient mice from influenza lethality.\",\n      \"method\": \"Genetic knockout (Birc3-/- mice), Ripk3-/- and Ripk1 inhibitor epistasis, histopathology, viral replication assay, hematopoietic cell transfer\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with multiple genetic rescue experiments (Ripk3 KO, Ripk1 inhibitor, FasL/TRAIL deletion); defines precise pathway position\",\n      \"pmids\": [\"24439895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP11 is a deubiquitylase that directly stabilizes cIAP2 protein by removing ubiquitin chains, preventing Smac mimetic-induced cIAP2 degradation. High USP11 expression correlates with cIAP2 stability and resistance to Smac mimetic-induced apoptosis. TNFα/JNK pathway induces USP11 expression to maintain cIAP2 stability as an alternative survival pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, USP11 overexpression/knockdown, apoptosis assay, xenograft model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP of USP11-cIAP2, functional ubiquitination assay, KD with phenotype; single lab\",\n      \"pmids\": [\"25613375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In BIRC3-disrupted CLL cells (via inactivating mutations or gene deletions removing the RING domain), constitutive non-canonical NF-κB signaling is activated, consistent with loss of cIAP2 E3 ligase-mediated NIK degradation. BIRC3 disruption associates specifically with fludarabine-refractory CLL.\",\n      \"method\": \"Biochemical analysis of non-canonical NF-κB activation (NIK stabilization, p52 processing) in primary CLL samples with BIRC3 mutations/deletions\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — biochemical pathway activation assay in primary patient samples correlating RING-domain loss with NIK/NF-κB activation; single lab, supports mechanistic model\",\n      \"pmids\": [\"22308293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"cIAP2 functions as an E3 ubiquitin ligase that promotes polyubiquitination and proteasome-mediated degradation of hepatitis B virus (HBV) polymerase. cIAP2 binds HBV polymerase, promotes its K48-linked ubiquitination, reduces encapsidation of HBV pregenomic RNA, and thereby inhibits HBV replication. An E3 ligase-deficient cIAP2 mutant loses this antiviral activity.\",\n      \"method\": \"Overexpression/knockdown of cIAP2, co-immunoprecipitation of cIAP2-polymerase, ubiquitination assay, proteasome inhibitor, HBV replication intermediates assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay with E3-dead mutant, functional viral replication assay; single lab\",\n      \"pmids\": [\"21865390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NPD1 (neuroprotectin D1) induces nuclear translocation of cREL, which in turn mediates BIRC3 transcription. cREL-driven BIRC3 expression is required for NPD1-induced neural cell survival against oxidative stress; BIRC3 silencing prevents NPD1 survival induction. In vivo, brain NPD1 biosynthesis and neuronal BIRC3 abundance are increased by DHA after ischemic stroke.\",\n      \"method\": \"cREL nuclear translocation assay, BIRC3 promoter-reporter, siRNA knockdown of BIRC3, retinal pigment epithelial cell oxidative stress assay, in vivo stroke model with DHA treatment\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear translocation assay, promoter reporter, functional siRNA knockdown; single lab with in vitro and in vivo components\",\n      \"pmids\": [\"25633199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"An ARIA (apoptosis regulator through modulating IAP expression) protein promotes proteasomal degradation of cIAP2 in endothelial cells without affecting cIAP2 mRNA. ARIA interacts with 20S proteasome subunit alpha-7. ARIA knockdown increases cIAP2 protein and reduces endothelial apoptosis; simultaneous knockdown of both cIAP1 and cIAP2 abolishes the ARIA-knockdown anti-apoptotic effect.\",\n      \"method\": \"siRNA knockdown, protein stability assay, yeast two-hybrid (ARIA-proteasome interaction), overexpression, co-immunoprecipitation, in vivo angiogenesis models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double cIAP1/2 KD), proteasomal degradation assay, yeast two-hybrid for interaction; single lab\",\n      \"pmids\": [\"19416853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The long 3' UTR of BIRC3 mRNA (upregulated in leukemia) is required for CXCR4-mediated B cell migration. The long 3' UTR enables formation of additional protein complexes not present when BIRC3 is encoded from short 3' UTR mRNA, including interactors regulating CXCR4 trafficking. RNA-binding proteins Staufen and HuR cooperatively bind the long 3' UTR to mediate this 3'-UTR-dependent complex formation.\",\n      \"method\": \"Mass spectrometry interactome of BIRC3 from long vs. short 3' UTR mRNA, CXCR4 trafficking assay, B cell migration assay, Staufen/HuR RIP assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry interactome with functional validation (migration, CXCR4 trafficking); single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30948266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cell cycle-dependent expression of cIAP2 peaks at G2/M phase, mediated by a bipartite CDE/CHR element in the cIAP2 promoter. This G2/M-specific cIAP2 expression is enhanced by NF-κB but occurs independently of NF-κB. Selective downregulation of cIAP2 in nocodazole-arrested cells increases susceptibility to apoptosis, establishing a survival function specific to mitotic arrest.\",\n      \"method\": \"Cell cycle synchronization, promoter deletion/mutagenesis (CDE/CHR elements), siRNA knockdown, apoptosis assay in mitotically arrested cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis with cell-cycle synchronization, functional siRNA KD; single lab\",\n      \"pmids\": [\"16813569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"cIAP2 functions as an E3 ligase for MRE11 in bladder cancer cells following HDAC inhibition. cIAP2 is upregulated in response to HDAC inhibition, binds MRE11, promotes altered MRE11 ubiquitination and downregulation, and mediates radiosensitization. Overexpression of cIAP2 alone recapitulates the effects of HDAC inhibition on MRE11 levels.\",\n      \"method\": \"Co-immunoprecipitation (cIAP2-MRE11), ubiquitination assay, cIAP2 overexpression, radiosensitization assay, HDAC inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional radiosensitization readout; single lab\",\n      \"pmids\": [\"28363998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BIRC3 expression is upregulated in GBM in response to irradiation and temozolomide treatment through STAT3 and PI3K signaling pathways. BIRC3 upregulation promotes apoptosis evasion and therapeutic resistance; selective inhibition of BIRC3 reverses resistance.\",\n      \"method\": \"BIRC3 expression analysis after RT/TMZ, pathway inhibitor treatment (STAT3/PI3K), functional apoptosis assay in GBM cell lines and in vivo xenografts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological pathway inhibitors with functional readout, single lab; STAT3/PI3K as upstream regulators established by inhibitor studies\",\n      \"pmids\": [\"26888114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"cIAP2 upregulation in CRC cells following Fusobacterium nucleatum infection is mediated via the TLR4/NF-κB pathway, and this cIAP2 upregulation confers resistance to 5-fluorouracil both in vitro and in vivo.\",\n      \"method\": \"Whole genome microarray, siRNA knockdown of BIRC3, in vitro and in vivo 5-FU sensitivity assay, NF-κB pathway inhibition\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with functional chemosensitivity assay in vitro and xenograft; single lab, TLR4/NF-κB epistasis by pathway inhibition\",\n      \"pmids\": [\"30630498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"cIAP2 ubiquitinates RIPK1 to maintain NF-κB signaling and cell survival. Combined in vivo deletion of cIap2 from cIap1-deficient adult mice causes rapid inflammation and aberrant caspase-8-dependent cell death in intestine and liver; Casp8 + Ripk3 double deletion prevents this cell death and partially reduces inflammation. Residual inflammation in cIAP1/2-deficient mice is reduced by NIK inhibition.\",\n      \"method\": \"Conditional double-KO mouse (inducible cIap2 deletion in cIap1-KO background), Casp8/Ripk3/Mlkl genetic deletion epistasis, NIK inhibitor, histopathology, cleaved caspase immunoblot\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with multiple KO combinations defining caspase-8-dependent cell death as primary cIAP1/2 target; rigorous in vivo design\",\n      \"pmids\": [\"31141691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP35 is a deubiquitylase that directly interacts with and stabilizes BIRC3 by removing K48-linked polyubiquitin chains, preventing proteasomal degradation. USP35 overexpression increases BIRC3 abundance and confers resistance to cisplatin-induced apoptosis in NSCLC cells; USP35 knockdown reduces BIRC3 and sensitizes cells to cisplatin.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-specific), USP35 overexpression/knockdown, BIRC3 protein stability assay, apoptosis assay\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP and ubiquitination assay with functional apoptosis readout; single lab\",\n      \"pmids\": [\"35022505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pellino-1 E3 ubiquitin ligase directly interacts with cIAP2 and stabilizes it through Lys63-linked polyubiquitination, conferring chemoresistance to cisplatin and paclitaxel in lung cancer cells. Pellino-1-mediated chemoresistance is dependent on cIAP2 induction.\",\n      \"method\": \"Co-immunoprecipitation, K63-ubiquitination assay, Pellino-1 overexpression/knockdown, chemosensitivity assay, epistasis with cIAP2 knockdown\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP and ubiquitination assay with epistasis (cIAP2 KD rescues Pellino-1 effect); single lab\",\n      \"pmids\": [\"27248820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"cIAP2 knockdown in mammary epithelial cells activates MDM2 through increased SUMOylation and IKKα/β-dependent phosphorylation, causing p53 degradation. cIAP2 prevents IKKα/β-mediated MDM2 activation; concomitant IKKα/β inhibition rescues p53 levels after cIAP2 knockdown. cIAP2 knockdown disrupts the PIAS1-IKKα interaction required to prevent MDM2 SUMOylation.\",\n      \"method\": \"siRNA knockdown, MDM2 SUMOylation assay, IKKα/β inhibition, immunoprecipitation of PIAS1-IKKα complex, p53 level rescue by Nutlin-3a\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (SUMOylation, phosphorylation, Co-IP) with genetic epistasis; single lab\",\n      \"pmids\": [\"23032264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BIRC3 mutations that remove the RING domain (abolishing E3 ubiquitin ligase activity) confer direct oncogenic/transforming potential in a wide range of epithelial tumor cell lines. This transforming function is largely independent of canonical NF-κB activation. NIK is an important but not exclusive mediator of BIRC3-mutant-driven carcinogenesis, acting through pathways other than NF-κB.\",\n      \"method\": \"Transformation assay (focus formation, anchorage-independent growth), RING domain mutants, NF-κB reporter, NIK knockdown epistasis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transformation assay with multiple RING mutants and NIK epistasis; single lab, functional readouts\",\n      \"pmids\": [\"26094954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"H. pylori CagA protein induces resistance to caspase-3-mediated apoptosis in gastric epithelial cells via Brd4-dependent synthesis of a BIRC3 enhancer RNA (eRNA), which drives BIRC3 mRNA and cIAP2 protein upregulation. Depletion of BIRC3 eRNA or inhibition of Brd4 reverses H. pylori-induced cIAP2 induction and apoptosis resistance. CagA-deficient H. pylori mutant fails to activate BIRC3 eRNA synthesis.\",\n      \"method\": \"siRNA knockdown of BIRC3 eRNA and BIRC3, Brd4 inhibitor, CagA-deficient bacterial mutant, caspase-3 activation assay, ChIP for Brd4 at BIRC3 enhancer\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — eRNA knockdown with functional apoptosis readout, Brd4 ChIP, genetic bacterial mutant; single lab\",\n      \"pmids\": [\"32820150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"During anastasis (recovery from executioner caspase activation), colorectal cancer cells upregulate cIAP2 and activate NF-κB. This elevated cIAP2/NF-κB signaling persists in anastatic cells and is required both for initial survival of caspase activation and for subsequent enhanced migration, metastasis, and chemoresistance.\",\n      \"method\": \"Lineage-tracing system to isolate anastatic cells, cIAP2 knockdown, NF-κB inhibition, caspase activation reporter, migration and chemoresistance assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lineage tracing with defined molecular mechanism (cIAP2/NF-κB), functional KD epistasis; single lab\",\n      \"pmids\": [\"37391410\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BIRC3 (cIAP2) is a RING-domain E3 ubiquitin ligase that suppresses apoptosis and inflammation primarily by ubiquitinating key signaling substrates: it maintains K63-linked polyubiquitination of RIP1/RIPK1 (promoting canonical NF-κB survival signaling and preventing caspase-8-dependent cell death), mediates K48-linked ubiquitination of NIK to drive its proteasomal degradation and thus suppress non-canonical NF-κB, ubiquitinates RIP2 for NOD1/2 innate immune signaling, mediates K63-linked ubiquitination of caspase-1 for inflammasome activation, and acts as an E3 for additional substrates including BCL10, IKKε, MRE11, and HBV polymerase; its subcellular localization is regulated by CRM1-dependent nuclear export and TRAF2-mediated cytoplasmic retention; its mRNA undergoes stress-modulated ribosome shunting for translation and is destabilized by TTP binding to a 3' UTR ARE; and deubiquitylases USP11 and USP35 stabilize the protein by removing ubiquitin chains, while loss of its RING-domain E3 activity (by mutation or the cIAP2-MALT1 oncofusion) constitutively activates non-canonical NF-κB and can confer direct oncogenic transformation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BIRC3 (cIAP2) is a RING-domain E3 ubiquitin ligase that governs the balance between cell survival, apoptosis, necroptosis, and inflammatory signaling by ubiquitinating key signaling substrates [#3, #5, #33]. Although its BIR domains bind caspases-3, -7, and -9, critical substitutions relative to XIAP render it a caspase-binding scaffold rather than a direct caspase inhibitor [#1]. Its dominant survival function is the E3 ligase-dependent K63-linked ubiquitination of RIP1/RIPK1, which it performs redundantly with cIAP1 after recruitment to the TNFR1 signalosome; this maintains canonical NF-\\u03baB survival signaling and prevents RIP1 from binding caspase-8 to trigger cell death [#3, #4, #33]. In parallel, cIAP2 works with TRAF2/TRAF3 to mediate constitutive proteasomal degradation of NIK, suppressing non-canonical NF-\\u03baB; loss of its RING-domain E3 activity stabilizes NIK and constitutively activates this pathway, driving B-cell hyperplasia and direct oncogenic transformation [#5, #11, #37]. Beyond these axes it ubiquitinates BCL10 to restrain antigen-receptor NF-\\u03baB signaling [#9], RIP2 for NOD1/2 innate immunity [#6], caspase-1 for inflammasome activation [#8], and IKK\\u03b5 to support its kinase activity and transforming function [#13]. By limiting RIP3/RIP1 necrosome formation, cIAP2 also restrains RIPK3-dependent necroptosis, protecting against influenza A-induced epithelial death [#21, #22]. The crystal structure of the TRAF2:cIAP2 complex shows a TRAF2 trimer engaging one cIAP2 molecule, with TRAF1 incorporation strengthening the interaction [#7]. Its abundance is set by deubiquitylases USP11 and USP35, which remove ubiquitin chains to stabilize the protein and confer therapeutic resistance [#23, #34]. BIRC3 is transcriptionally driven by NF-\\u03baB family members [#17, #18], and its inactivating RING-domain mutations are associated with fludarabine-refractory chronic lymphocytic leukemia [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the first biochemical activity for cIAP2 by testing whether it directly inhibits caspases, the central question for an 'IAP' family member.\",\n      \"evidence\": \"In vitro binding/caspase activity assays, cell-free cytochrome-c extracts, and overexpression in cells\",\n      \"pmids\": [\"9384571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not assess physiological stoichiometry or endogenous relevance\", \"Conflicted with later structural analysis of caspase-binding sites\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revised the caspase-inhibitor model by showing cIAP2 BIR domains bind but do not inhibit caspases, reframing it as a scaffold rather than an effector inhibitor.\",\n      \"evidence\": \"In vitro binding/inhibition assays with site-directed mutagenesis swapping in XIAP residues\",\n      \"pmids\": [\"16339151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish what the caspase-binding scaffold does in cells\", \"Functional consequence of caspase binding without inhibition unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified cIAP2 as an E3 ubiquitin ligase acting on RIP1, shifting the field from apoptosis inhibition to ubiquitin-mediated signaling control.\",\n      \"evidence\": \"In vitro ubiquitination assay, ectopic expression with proteasome inhibitor, and RING-domain deletion; separately, CRM1-dependent nuclear export and TRAF2 cytoplasmic retention defined\",\n      \"pmids\": [\"15147886\", \"15265700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Initial study emphasized degradative RIP1 turnover rather than non-degradative chains\", \"Functional role of nuclear pool of cIAP2 not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended E3 substrate range to BCL10 and tied loss of E3 activity to the cIAP2-MALT1 oncofusion, providing the first link between E3 inactivation and lymphomagenesis.\",\n      \"evidence\": \"In vitro ubiquitination of BCL10, NF-\\u03baB reporter, and MALT lymphoma patient sample analysis\",\n      \"pmids\": [\"16395405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the fusion drives oncogenesis beyond BCL10 stabilization unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the dual NF-\\u03baB roles: cIAP2 maintains K63-ubiquitinated RIP1 for canonical survival signaling at TNFR1, and degrades NIK with TRAF2/3 to suppress non-canonical signaling.\",\n      \"evidence\": \"Genetic KO/RNAi, TNFR1-complex Co-IP, RIP1/IKK\\u03b2 assays, NIK degradation, and Smac mimetic functional assays\",\n      \"pmids\": [\"18570872\", \"18697935\", \"18997794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with cIAP1 complicates assigning cIAP2-specific contributions\", \"Chain-type switching between K63 and K48 on shared substrates not fully resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated cIAP2 is required for RIP2 K63-ubiquitination and NOD1/2 innate immune signaling in vivo, broadening its role to pattern-recognition immunity.\",\n      \"evidence\": \"Birc3-/- mice, RNAi, RIP2 ubiquitination assay, and in vivo MDP/colitis model; separately, NEMO-downstream genotoxic NF-\\u03baB role by RNAi epistasis\",\n      \"pmids\": [\"19464198\", \"19223549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing cIAP2 from cIAP1/XIAP in genotoxic pathway remains correlative\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided atomic-resolution insight into how cIAP2 is recruited to signaling complexes via TRAF2, and how TRAF1 regulates the interaction.\",\n      \"evidence\": \"X-ray crystallography of TRAF2:cIAP2 and TRAF1:TRAF2:cIAP2 complexes with interface mutagenesis\",\n      \"pmids\": [\"20385093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures do not capture catalytically engaged RING/E2 state\", \"Dynamics of recruitment to active signalosomes not visualized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed loss of cIAP2 E3 activity alone stabilizes NIK and drives non-canonical NF-\\u03baB and MALT-lymphoma-like B-cell pathology in vivo, and linked RING-domain disruption to fludarabine-refractory CLL.\",\n      \"evidence\": \"E3-inactive knock-in mice, B-cell phenotyping, and biochemical analysis of NIK/p52 in primary CLL samples; also caspase-1 inflammasome ubiquitination and translational control studies\",\n      \"pmids\": [\"21048983\", \"22308293\", \"22195745\", \"18195037\", \"16813569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How loss of E3 activity selectively activates non-canonical over canonical signaling not fully mechanistic\", \"Cell-cycle-coupled survival role (G2/M) not integrated with signaling roles\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established cIAP2 as a brake on RIPK3-dependent necroptosis by post-transcriptionally limiting necrosome components, and expanded substrate range to viral and tumor-suppressor pathways.\",\n      \"evidence\": \"KO macrophages with Smac mimetic/RIP1 inhibitor epistasis; HBV polymerase ubiquitination assays; MDM2/p53 SUMOylation biochemistry\",\n      \"pmids\": [\"22576661\", \"21865390\", \"23032264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of post-transcriptional RIP3 control undefined\", \"MDM2/p53 link rests on RNAi in one system\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the in vivo physiological consequence of necroptosis restraint, showing cIAP2 protects airway epithelium from RIPK3-mediated death during influenza.\",\n      \"evidence\": \"Birc3-/- mice with Ripk3 KO, RIPK1 inhibitor, and FasL/TRAIL deletion rescue\",\n      \"pmids\": [\"24439895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether protection is purely E3-dependent not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated cIAP2 abundance is post-translationally tuned by deubiquitylases and an opposing E3, and expanded substrates to DNA-repair factor MRE11 with therapeutic relevance.\",\n      \"evidence\": \"USP11 Co-IP/ubiquitination with xenograft; ARIA-proteasome degradation; Pellino-1 K63 stabilization; cIAP2-MRE11 Co-IP and radiosensitization\",\n      \"pmids\": [\"25613375\", \"19416853\", \"27248820\", \"28363998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy among competing stabilizing/destabilizing regulators in vivo unknown\", \"MRE11 ubiquitination chain-type and site not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined how cIAP1/2 loss together triggers caspase-8-dependent intestinal/hepatic pathology in vivo, and uncovered a 3'-UTR-dependent moonlighting role in CXCR4-mediated B-cell migration.\",\n      \"evidence\": \"Inducible cIap1/cIap2 double-KO mice with Casp8/Ripk3 epistasis and NIK inhibition; BIRC3 long-3'UTR interactome with Staufen/HuR and migration assays\",\n      \"pmids\": [\"31141691\", \"30948266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"3'-UTR-dependent complex composition only partially characterized\", \"Relationship between protein E3 function and mRNA-scaffolding role unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reinforced deubiquitylase-mediated stabilization as a resistance mechanism, with USP35 removing K48 chains to protect cIAP2 and confer cisplatin resistance.\",\n      \"evidence\": \"Co-IP, K48-specific ubiquitination assay, and apoptosis assays in NSCLC cells\",\n      \"pmids\": [\"35022505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether USP11 and USP35 act redundantly or context-specifically not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed elevated cIAP2/NF-\\u03baB signaling enables anastatic recovery from executioner caspase activation, conferring metastatic and chemoresistant properties.\",\n      \"evidence\": \"Lineage-tracing isolation of anastatic CRC cells with cIAP2 knockdown and NF-\\u03baB inhibition\",\n      \"pmids\": [\"37391410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate driving anastatic survival not identified\", \"Single cancer-cell system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse upstream regulators (transcriptional, translational, and stability-based) integrate to set cIAP2 levels at specific subcellular sites, and how a single RING ligase selects among K63 versus K48 chains on its many substrates in vivo, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for chain-type selectivity across substrates\", \"Functional significance of nuclear cIAP2 pool undefined\", \"cIAP1/cIAP2 division of labor incompletely resolved in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2, 3, 6, 9, 13, 25, 30]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 6, 8, 9, 13, 25, 30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 5, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 21, 22, 33]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 24, 37]}\n    ],\n    \"complexes\": [\"TRAF2:cIAP2 complex\", \"TRAF1:TRAF2:cIAP2 complex\", \"TNFR1 signalosome\"],\n    \"partners\": [\"TRAF2\", \"TRAF3\", \"RIPK1\", \"NIK\", \"BCL10\", \"IKBKE\", \"USP11\", \"USP35\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}