{"gene":"ARL6IP5","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2001,"finding":"GTRAP3-18 (ARL6IP5) specifically interacts with the carboxy-terminal intracellular domain of EAAC1 (neuronal glutamate transporter), localizes to the cell membrane and cytoplasm, and increasing GTRAP3-18 expression reduces EAAC1-mediated glutamate transport by lowering substrate affinity.","method":"Co-immunoprecipitation, functional transport assay in cells, overexpression","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction mapping, functional transport assay, replicated by multiple subsequent labs","pmids":["11242046"],"is_preprint":false},{"year":2007,"finding":"GTRAP3-18 is a resident endoplasmic reticulum protein that delays ER exit of EAAC1 and other excitatory amino acid transporter family members; it self-associates via hydrophobic domain interactions in the ER membrane and uses cytoplasmic C-terminal interactions to regulate trafficking.","method":"Subcellular fractionation, ER exit assay (VSVG transport), co-immunoprecipitation, domain deletion mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, trafficking assay, mutagenesis) in single study, consistent with independent reports","pmids":["18167356"],"is_preprint":false},{"year":2007,"finding":"GTRAP3-18 at the plasma membrane negatively and dominantly regulates intracellular glutathione content by controlling EAAC1-mediated cysteine uptake; increasing cell-surface GTRAP3-18 (via methyl-β-cyclodextrin) decreases GSH, while decreasing it (via antisense oligonucleotides) increases GSH.","method":"Pharmacological manipulation of membrane GTRAP3-18 levels, antisense knockdown, GSH measurement, oxidative stress assay","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional manipulation (increase and decrease), replicated in vivo and in vitro across multiple papers","pmids":["17646425","18799673","21373771"],"is_preprint":false},{"year":2008,"finding":"GTRAP3-18 acts as a negative regulator of Rab1, inhibiting ER-to-Golgi trafficking; overexpression reduces VSVG transport rate, slows cargo concentration of EAAC1 into transport complexes, and inhibits neurite outgrowth in CAD cells—effects rescued by Rab1 co-expression.","method":"VSVG transport assay, Brefeldin A treatment, neurite length measurement, rescue by Rab1 co-expression","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts, rescue experiment with Rab1 provides epistasis evidence","pmids":["18363836"],"is_preprint":false},{"year":2008,"finding":"GTRAP3-18 interacts with EAAC1 at the plasma membrane and dominantly determines intracellular neuronal glutathione levels; genetic reduction of GTRAP3-18 in mouse brain increases plasma membrane EAAC1 and raises brain GSH, while overexpression suppresses GSH.","method":"Genetic manipulation (transgenic mice), co-immunoprecipitation, GSH measurement in primary neurons and mouse brain","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model plus in vitro co-IP, replicated in multiple subsequent studies","pmids":["18799673"],"is_preprint":false},{"year":2009,"finding":"JWA interacts with XRCC1 and functions as a base excision repair protein for oxidative-stress-induced DNA single-strand breaks: JWA is translocated to the nucleus by XRCC1, co-localizes with XRCC1 foci after DNA damage, regulates XRCC1 transcriptionally via MAPK/E2F1, and protects XRCC1 from ubiquitination and proteasomal degradation.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, SSB repair assay (comet assay), ubiquitination assay, reporter assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods establishing direct physical interaction, functional repair assay, and post-translational mechanism","pmids":["19208635"],"is_preprint":false},{"year":2009,"finding":"JWA knockdown increases melanoma cell adhesion and invasion and promotes metastatic colony formation in vivo by intensifying integrin αVβ3 signaling through regulation of nuclear factor Sp1.","method":"siRNA knockdown, invasion/adhesion assays, in vivo metastasis model (B16-F10, A375), Western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with pathway placement (integrin αVβ3/Sp1), single lab","pmids":["19946336"],"is_preprint":false},{"year":2007,"finding":"JWA is required for rearrangement of F-actin cytoskeleton and activation of MAPK cascades (ERK, downstream FAK and COX-2) induced by As2O3 and PMA; JWA overexpression alone inhibits cancer cell migration, while JWA deficiency accelerates migration. SDR-SLR motifs of JWA are critical for MAPK cascade activation and cell migration.","method":"Overexpression and antisense knockdown, cell migration assay (wound healing/transwell), F-actin staining, MAPK phosphorylation western blot, domain mutagenesis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation plus domain mutagenesis, single lab","pmids":["17336041"],"is_preprint":false},{"year":2011,"finding":"GTRAP3-18-deficient mice show increased EAAC1 expression at the plasma membrane, increased neuronal GSH content, and neuroprotection against oxidative stress, as well as improved motor/spatial learning and memory.","method":"Gene-targeting knockout mice, membrane fractionation, GSH measurement, behavioral testing, oxidative stress challenge","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal readouts, replicates prior pharmacological findings","pmids":["22210510"],"is_preprint":false},{"year":2014,"finding":"JWA regulates cisplatin-induced DNA damage and apoptosis through the CK2-phospho-XRCC1-XRCC1 pathway: in normal cells JWA upregulates XRCC1, but in cisplatin-resistant gastric cancer cells JWA promotes XRCC1 degradation; mutation of CK2-targeted 518S/519T/523T residues of XRCC1 blocks this negative regulation.","method":"Site-directed mutagenesis of XRCC1 phosphorylation sites, Western blot, cell viability assay, cisplatin-resistant cell models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site mutagenesis identifies specific CK2-XRCC1 mechanism, single lab","pmids":["25476899"],"is_preprint":false},{"year":2018,"finding":"E3 ubiquitin ligase RNF185 directly interacts with JWA and promotes its ubiquitination at K158, leading to proteasomal degradation; RNF185 expression is negatively correlated with JWA in gastric cancer tissues.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K158), Western blot, in vivo metastasis model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and site-specific ubiquitination identified, single lab","pmids":["29481911"],"is_preprint":false},{"year":2017,"finding":"JWA suppresses TRAIL-induced apoptosis in cisplatin-resistant gastric cancer cells by promoting ubiquitination of death receptor 4 (DR4) at K273 via upregulation of the E3 ubiquitin ligase MARCH8; JWA and DR4 protein levels are negatively correlated in gastric cancer tissues.","method":"Overexpression/knockdown, ubiquitination assay, site-directed mutagenesis (DR4 K273), Western blot, apoptosis assay","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific ubiquitination and E3 ligase identified, single lab","pmids":["28671676"],"is_preprint":false},{"year":2014,"finding":"Arl6ip5 is expressed in osteoblasts and functions as an ER calcium regulator controlling calmodulin signaling for osteoblast proliferation; Arl6ip5 deficiency induces ER stress and ER stress-mediated apoptosis (via CHOP), impairs osteoblast differentiation, and increases RANKL expression to enhance osteoclastogenesis.","method":"Conditional knockout mice, calcium flux assay, ER stress markers (Western blot), siRNA knockdown, histomorphometry, in vitro osteoblast/osteoclast assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout plus multiple in vitro mechanistic readouts, single lab","pmids":["25321471"],"is_preprint":false},{"year":2015,"finding":"Overexpression of Arl6ip5 in osteoblasts retains RANKL in the ER, decreases soluble RANKL secretion, and inhibits osteoclastogenesis; Arl6ip5 physically binds RANKL and disrupts the RANKL-OPG complex. Deletion of the NH2-terminal 1–36 amino acids of Arl6ip5 abolishes its interaction with RANKL and restores RANKL secretion.","method":"Co-immunoprecipitation, domain deletion mutagenesis, conditioned medium RANKL ELISA, osteoclast formation assay, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding identified with deletion mutagenesis, functional consequence on RANKL trafficking, single lab","pmids":["26220341"],"is_preprint":false},{"year":2017,"finding":"GTRAP3-18 interacts with pro-opiomelanocortin (POMC) in the ER, retaining it and reducing α-MSH secretion; GTRAP3-18-deficient mice show hypophagia, lean bodies, elevated α-MSH levels, and AMPK inhibition, effects reversed by melanocortin 4 receptor antagonist.","method":"FRET (fluorescence resonance energy transfer) interaction assay, GTRAP3-18-deficient mice, intraperitoneal glucose tolerance test, intracerebroventricular antagonist infusion, serum α-MSH measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET establishes direct interaction, KO mouse model with pharmacological rescue, single lab","pmids":["28904020"],"is_preprint":false},{"year":2018,"finding":"Astrocytic JWA deficiency reduces expression of the glutamate transporter GLT-1 and glutamate uptake in vivo and in vitro; this occurs via suppression of MAPK and PI3K/CREB signaling. JWA-increased GLT-1 expression is abolished by MEK and PI3K inhibitors and by CREB silencing.","method":"Astrocyte-specific conditional JWA knockout mice, in vitro GLT-1 expression assay, pharmacological pathway inhibitors, CREB siRNA, MPTP/paraquat neurotoxin models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with pharmacological epistasis, single lab","pmids":["29500411"],"is_preprint":false},{"year":2011,"finding":"JWA is required for chronic morphine-induced maintenance of delta opioid receptor (DOR) stability via the ubiquitin-proteasome pathway; JWA knockdown in rats reduces morphine withdrawal response and suppresses DOR expression as well as DARPP-32 and MAP kinase activation.","method":"siRNA knockdown in rats, in vitro chronic morphine cell model, Western blot, ubiquitin-proteasome pathway assay, behavioral withdrawal scoring","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown plus in vitro mechanistic follow-up identifying ubiquitin-proteasome pathway, single lab","pmids":["21600884"],"is_preprint":false},{"year":2024,"finding":"JWA physically occupies the ferritin binding site of NCOA4 (nuclear receptor coactivator 4), thereby inhibiting NCOA4-mediated ferritinophagy and reducing iron-dependent ferroptosis in dopaminergic neurons; molecular docking, co-immunoprecipitation, and immunofluorescence confirm direct JWA-NCOA4 interaction.","method":"Molecular docking, co-immunoprecipitation, immunofluorescence, genetic manipulation (JWA overexpression/knockdown), cellular and animal PD models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods confirming direct interaction (docking + co-IP + IF), functional ferroptosis readout, single lab","pmids":["38744191"],"is_preprint":false},{"year":2025,"finding":"ARL6IP5 is an ER membrane-shaping protein containing the PRA1 domain; upon overexpression it induces extensive ER tubular networks and constricts the ER membrane (excluding luminal ER enzymes from tubules). ARL6IP5 knockdown impairs ER morphology and reduces FAM134B-mediated ER-phagy flux. Disruption of putative short hairpin structures in the PRA1 domain abolishes membrane constriction. ARL6IP5 and ARL6IP1 (an RHD-containing protein) can functionally substitute for each other in ER shaping.","method":"siRNA knockdown, overexpression, live-cell imaging of ER morphology, ER-phagy flux assay, domain mutagenesis, microtubule depolymerization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (live imaging, flux assay, domain mutagenesis, rescue experiments), defines novel ER membrane-shaping mechanism, single lab but rigorous","pmids":["40209949"],"is_preprint":false},{"year":2023,"finding":"ARL6IP5 induces autophagy and reduces α-synuclein aggregate burden by stabilizing free ATG12 (preventing its ubiquitination and degradation) and enhancing Rab1-dependent autophagosome initiation and elongation.","method":"ARL6IP5 overexpression/knockdown, autophagic flux assay, ATG12 ubiquitination assay, co-immunoprecipitation, cellular PD model (A53T α-synuclein)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mechanistic interaction (ATG12 stabilization, Rab1-dependence) with functional autophagy readout, single lab","pmids":["37445677"],"is_preprint":false},{"year":2024,"finding":"ARL6IP5 induces reticulophagy to reduce PrPSc burden and alleviate ER stress; ARL6IP5-induced reticulophagy depends on Ca2+-mediated AMPK activation and involves physical interaction with reticulophagy receptor CALCOCO1 and lysosomal marker LAMP1 for lysosomal degradation.","method":"Overexpression/knockdown in prion-infected cells (RML-ScN2a), autophagic flux assay, co-immunoprecipitation (CALCOCO1, LAMP1), AMPK inhibition, Ca2+ measurement","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction with CALCOCO1 identified, Ca2+/AMPK pathway established, single lab","pmids":["39394963"],"is_preprint":false},{"year":2018,"finding":"Rab1a can rescue the cytotoxicity caused by PRAF3 (ARL6IP5) overexpression, presumably by positively regulating ER-to-Golgi trafficking and counteracting the negative modulation by PRAF3.","method":"Co-expression rescue assay, cell viability assay","journal":"Biochemistry and biophysics reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single rescue assay, no direct binding confirmed in this paper, mechanism inferred","pmids":["29872729"],"is_preprint":false},{"year":2016,"finding":"JWA suppresses EGF-induced cell migration and actin cytoskeletal rearrangement in HER2-overexpressing gastric cancer cells by downregulating HER2 expression through ERK activation and consequent PEA3 upregulation; modulation of HER2 by JWA is ERK/PEA3-dependent.","method":"Transwell migration assay, G-LISA (Rho GTPase activity), Western blot, real-time PCR, EMSA, luciferase reporter assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods establishing ERK/PEA3 pathway for HER2 regulation, single lab","pmids":["27167206"],"is_preprint":false},{"year":2016,"finding":"JWA promotes HER2 degradation via the E3 ubiquitin ligase c-Cbl, representing a mechanism for JWA-induced HER2 downregulation that confers lapatinib resistance while reversing cisplatin resistance in gastric cancer cells.","method":"Western blot, co-immunoprecipitation (c-Cbl/HER2), overexpression/knockdown, cell viability assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP identifies c-Cbl as the degradation mechanism, replicated across two JWA/HER2 pathway papers","pmids":["27708243"],"is_preprint":false},{"year":2021,"finding":"JWA suppresses HER2 ubiquitination and proliferation of HER2-positive breast cancer through the E3 ubiquitin ligase SMURF1 (increased by JAC1-mediated decrease of NEDD4, the E3 ligase for SMURF1); JWA promotes HER2 ubiquitination at K716 via SMURF1.","method":"Ubiquitination assay (K716 site), Western blot, overexpression, in vitro and in vivo proliferation assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific ubiquitination (K716) and E3 ligase (SMURF1) identified, single lab","pmids":["33875644"],"is_preprint":false},{"year":2018,"finding":"JWA suppresses breast cancer cell invasion by negatively regulating cell-surface CXCR4 expression via proteasome-mediated degradation (not transcriptional inhibition); normalizing CXCR4 reverses JWA's inhibitory effect on invasion.","method":"Overexpression/knockdown, invasion assay, flow cytometry (surface CXCR4), proteasome inhibitor rescue, CXCR4 rescue experiment","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteasome dependence established, CXCR4 rescue provides functional epistasis, single lab","pmids":["29658570"],"is_preprint":false},{"year":2022,"finding":"JWA deficiency promotes NOTCH1 degradation via the ERK/FBXW7-mediated ubiquitin-proteasome pathway, thus disturbing the PPARγ/STAT5 axis and reducing intestinal stem cell function and epithelial cell lineage distribution.","method":"Jwa knockout mice, intestinal organoids, Western blot, proteasome assay, pathway inhibitor studies","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with defined pathway (ERK/FBXW7/NOTCH1), single lab","pmids":["36147468"],"is_preprint":false},{"year":2023,"finding":"JWA negatively regulates CD44 expression in lung cancer by inhibiting ubiquitination-mediated degradation of SP1 (Specificity Protein 1); nicotine downregulates JWA via the CHRNA5-mediated AKT pathway, leading to elevated SP1 and CD44.","method":"Western blot, ubiquitination assay, in vivo xenograft, siRNA/overexpression, pharmacological AKT pathway inhibition","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination mechanism and upstream CHRNA5/AKT pathway identified, in vivo validation, single lab","pmids":["37224781"],"is_preprint":false},{"year":2023,"finding":"JAC4 promotes NEDD4L stability via AMPK-mediated phosphorylation at Thr367; the WW domain of NEDD4L (E3 ubiquitin ligase) interacts with EGFR and promotes its ubiquitination at K716, leading to EGFR degradation; this cascade is initiated by JAC4 directly binding CTBP1 and blocking its nuclear translocation, thereby de-repressing JWA gene transcription.","method":"Co-immunoprecipitation, ubiquitination assay (K716), mass spectrometry, cellular thermal shift assay, molecular docking, qRT-PCR, in vivo xenograft","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple interactions identified (JAC4-CTBP1, AMPK-NEDD4L, NEDD4L-EGFR K716), single lab but several orthogonal methods","pmids":["37240137"],"is_preprint":false},{"year":2022,"finding":"JAC1 specifically binds YY1 and eliminates its transcriptional repression of the JWA gene; JAC1 also promotes ubiquitination and degradation of YY1, and disrupts the YY1-HSF1 interaction.","method":"Co-immunoprecipitation, ubiquitination assay, luciferase reporter assay, Western blot","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and ubiquitination of YY1 identified with multiple methods, single lab","pmids":["35383155"],"is_preprint":false},{"year":2008,"finding":"JWA knockdown attenuates arsenic trioxide (As2O3)-induced apoptosis in HeLa and MCF-7 cells; JWA is required for As2O3-induced mitochondrial transmembrane potential loss, caspase-9 activation, and MEK1/2, ERK1/2, and JNK phosphorylations. JWA expression is induced by intracellular ROS generated by As2O3.","method":"siRNA knockdown, apoptosis assay (caspase activity, mitochondrial membrane potential), MAPK phosphorylation western blot, ROS measurement","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined pro-apoptotic pathway placement via knockdown, single lab","pmids":["18387645"],"is_preprint":false},{"year":2014,"finding":"JWA deficiency in neurons (JWA-nKO mice) enhances neurogenesis (survival/migration of newborn neurons and neurite growth) and lowers the LTP threshold in hippocampal dentate gyrus via the FAK-PI3K-Akt-mTOR pathway; PI3K or FAK inhibition abolishes enhanced neurogenesis and LTP; telomerase inhibition suppresses both neurogenesis and LTP enhancement.","method":"Neuronal-specific JWA knockout mice, Morris water maze, LTP electrophysiology, BrdU labeling, pharmacological inhibitor epistasis (PI3K, FAK, mTOR), telomerase inhibitor","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with pharmacological epistasis defining FAK/PI3K/Akt/mTOR pathway, single lab","pmids":["25432888"],"is_preprint":false}],"current_model":"ARL6IP5/GTRAP3-18/JWA is a four-transmembrane PRA1-domain ER-resident protein that (1) retains and inhibits the neuronal glutamate/cysteine transporter EAAC1 in the ER, reducing its plasma membrane expression and thereby suppressing neuronal glutathione synthesis; (2) negatively regulates Rab1-dependent ER-to-Golgi trafficking and acts as an ER membrane-shaping protein whose PRA1 domain constricts ER tubules and is required for FAM134B-mediated ER-phagy; (3) interacts with POMC in the ER to regulate α-MSH secretion and food intake; (4) in the nucleus/cytoplasm functions as a scaffold for DNA base excision repair by multi-interacting with XRCC1 (protecting it from ubiquitination and transcriptionally upregulating it via MAPK/E2F1), while being itself ubiquitinated at K158 by RNF185 for proteasomal degradation; (5) modulates cell migration and actin cytoskeletal rearrangement via MAPK cascades (ERK/FAK/COX-2) and integrin αVβ3/Sp1 signaling; (6) regulates HER2 levels through ERK/PEA3 and c-Cbl-mediated ubiquitination, and promotes DR4 ubiquitination at K273 via MARCH8 to suppress TRAIL-induced apoptosis; and (7) protects dopaminergic neurons by binding the ferritin-binding site of NCOA4 to inhibit ferritinophagy and ferroptosis."},"narrative":{"mechanistic_narrative":"ARL6IP5 (GTRAP3-18/JWA/PRAF3) is a four-transmembrane PRA1-domain endoplasmic reticulum protein that governs the ER residence and surface delivery of membrane transporters and acts more broadly as an ER membrane-shaping factor [PMID:18167356, PMID:40209949]. Its founding function is to bind the C-terminal intracellular domain of the neuronal glutamate/cysteine transporter EAAC1, retaining it in the ER and lowering its substrate affinity, thereby restricting EAAC1-mediated cysteine uptake and dominantly suppressing intracellular glutathione synthesis [PMID:11242046, PMID:18167356, PMID:17646425, PMID:18799673, PMID:21373771]; loss of ARL6IP5 in mice raises plasma-membrane EAAC1, elevates neuronal GSH, and confers neuroprotection against oxidative stress [PMID:18799673, PMID:22210510]. This trafficking control reflects a general role as a negative regulator of Rab1-dependent ER-to-Golgi transport, an activity rescued by Rab1 co-expression [PMID:18363836, PMID:29872729]. Through its PRA1 domain ARL6IP5 constricts ER tubules and shapes the tubular ER network, and is required for FAM134B-mediated ER-phagy [PMID:40209949]; consistent with a reticulophagy role, it promotes autophagy/ER-phagy via Ca2+/AMPK signaling and interaction with CALCOCO1 to clear pathological aggregates [PMID:39394963]. The protein also retains other secretory cargos in the ER, including POMC—limiting α-MSH secretion to influence food intake [PMID:28904020]—and RANKL, decreasing soluble RANKL and inhibiting osteoclastogenesis [PMID:26220341], while controlling ER calcium and CHOP-dependent ER stress in osteoblasts [PMID:25321471]. In a distinct nuclear/cytoplasmic role, ARL6IP5 (as JWA) functions in DNA single-strand-break base excision repair by interacting with XRCC1, being shuttled to the nucleus by XRCC1, transcriptionally upregulating XRCC1 via MAPK/E2F1, and protecting it from ubiquitin-proteasomal degradation [PMID:19208635]. ARL6IP5 protein levels are themselves controlled by RNF185-mediated ubiquitination at K158 [PMID:29481911]. Acting through MAPK cascades (ERK/FAK/COX-2) and integrin αVβ3/Sp1 signaling, it restrains cancer cell migration, adhesion, and invasion [PMID:19946336, PMID:17336041], and modulates the abundance of multiple receptors and death-pathway components by directing E3-ligase–dependent ubiquitination—promoting HER2 degradation via c-Cbl and SMURF1, and DR4 degradation via MARCH8 to suppress TRAIL-induced apoptosis [PMID:28671676, PMID:27708243, PMID:33875644]. It additionally protects dopaminergic neurons by occupying the ferritin-binding site of NCOA4 to inhibit ferritinophagy and ferroptosis [PMID:38744191].","teleology":[{"year":2001,"claim":"Established the first molecular function of ARL6IP5 by identifying it as a direct binding partner that down-regulates a neuronal glutamate transporter, answering what protein controls EAAC1 activity.","evidence":"Co-immunoprecipitation and functional transport assays with EAAC1 in cells","pmids":["11242046"],"confidence":"High","gaps":["Did not establish the subcellular site of inhibition","Stoichiometry and structural basis of the EAAC1 interaction unresolved"]},{"year":2007,"claim":"Defined ARL6IP5 as an ER-resident protein that delays ER exit of EAAC1, linking the inhibitory interaction to retention/trafficking rather than direct catalytic interference.","evidence":"Subcellular fractionation, VSVG ER exit assay, co-IP, and domain-deletion mutagenesis","pmids":["18167356"],"confidence":"High","gaps":["Did not define how self-association is regulated","Mechanism linking retention to transport affinity change unclear"]},{"year":2007,"claim":"Showed ARL6IP5 dominantly sets intracellular glutathione by controlling EAAC1-mediated cysteine uptake, connecting its trafficking role to redox homeostasis.","evidence":"Bidirectional pharmacological/antisense manipulation of GTRAP3-18 with GSH and oxidative-stress assays","pmids":["17646425","18799673","21373771"],"confidence":"High","gaps":["Did not separate plasma-membrane from ER pools of the protein mechanistically"]},{"year":2008,"claim":"Identified ARL6IP5 as a negative regulator of Rab1, broadening its role from EAAC1-specific retention to general ER-to-Golgi trafficking control.","evidence":"VSVG transport and neurite outgrowth assays rescued by Rab1 co-expression in CAD cells","pmids":["18363836"],"confidence":"High","gaps":["Did not demonstrate direct ARL6IP5-Rab1 binding","Did not define the GEF/GAP relationship to Rab1"]},{"year":2008,"claim":"Confirmed in vivo that ARL6IP5 dosage controls brain glutathione via plasma-membrane EAAC1, validating the redox role genetically.","evidence":"Transgenic mouse manipulation, co-IP, and GSH measurement in neurons and brain","pmids":["18799673"],"confidence":"High","gaps":["Behavioral/disease consequences not yet tested in this study"]},{"year":2009,"claim":"Revealed a nuclear/cytoplasmic moonlighting function in DNA repair, showing ARL6IP5 (JWA) scaffolds and stabilizes XRCC1 for base excision repair of oxidative single-strand breaks.","evidence":"Co-IP, IF co-localization, comet SSB-repair assay, ubiquitination and reporter assays","pmids":["19208635"],"confidence":"High","gaps":["How an ER transmembrane protein accesses the nucleus mechanistically not resolved","Direct vs indirect XRCC1 protection not fully distinguished"]},{"year":2007,"claim":"Placed ARL6IP5 upstream of MAPK-driven actin remodeling and cell migration, identifying motif requirements (SDR-SLR) for this signaling.","evidence":"Bidirectional manipulation, migration assays, F-actin staining, MAPK phospho-blots, domain mutagenesis","pmids":["17336041"],"confidence":"Medium","gaps":["Direct upstream receptor link not defined","Single lab"]},{"year":2009,"claim":"Connected the migration-suppressive function to anti-metastatic activity via integrin αVβ3/Sp1 signaling.","evidence":"siRNA, invasion/adhesion assays, in vivo melanoma metastasis model","pmids":["19946336"],"confidence":"Medium","gaps":["Direct molecular target between JWA and integrin signaling unidentified","Single lab"]},{"year":2011,"claim":"Demonstrated that ARL6IP5 knockout improves neuronal antioxidant capacity and cognition, establishing physiological relevance of the EAAC1/GSH axis.","evidence":"Gene-targeted knockout mice with fractionation, GSH, behavioral and oxidative-stress readouts","pmids":["22210510"],"confidence":"High","gaps":["Did not address non-neuronal roles of the protein"]},{"year":2011,"claim":"Extended ARL6IP5's receptor-stability role to delta opioid receptor maintenance during chronic morphine, implicating ubiquitin-proteasome control.","evidence":"siRNA knockdown in rats, chronic morphine cell model, ubiquitin-proteasome assays, behavioral withdrawal scoring","pmids":["21600884"],"confidence":"Medium","gaps":["Direct E3 ligase not identified","Mechanism of DOR stabilization not molecularly resolved"]},{"year":2014,"claim":"Established ARL6IP5 as an ER calcium/calmodulin regulator in osteoblasts whose loss triggers CHOP-dependent ER stress and apoptosis.","evidence":"Conditional knockout mice, calcium flux, ER stress markers, histomorphometry, in vitro osteoblast/osteoclast assays","pmids":["25321471"],"confidence":"Medium","gaps":["Molecular link between ARL6IP5 and ER Ca2+ handling not defined","Single lab"]},{"year":2014,"claim":"Showed ARL6IP5 modulates the CK2-phospho-XRCC1 axis context-dependently, switching from XRCC1 stabilization to degradation in cisplatin-resistant cells.","evidence":"Site-directed mutagenesis of XRCC1 CK2 sites, viability assays, resistant cell models","pmids":["25476899"],"confidence":"Medium","gaps":["Basis of the context-dependent switch unresolved","Single lab"]},{"year":2014,"claim":"Demonstrated neuronal ARL6IP5 loss enhances neurogenesis and lowers LTP threshold via a FAK-PI3K-Akt-mTOR pathway.","evidence":"Neuron-specific knockout mice with behavioral, LTP, BrdU, and pharmacological epistasis","pmids":["25432888"],"confidence":"Medium","gaps":["Direct molecular target initiating FAK/PI3K signaling unidentified","Single lab"]},{"year":2015,"claim":"Identified RANKL as an ER cargo retained by ARL6IP5, with an N-terminal (1-36) interaction controlling RANKL secretion and osteoclastogenesis.","evidence":"Co-IP, domain-deletion mutagenesis, RANKL ELISA, osteoclast formation assay","pmids":["26220341"],"confidence":"Medium","gaps":["Generality of cargo selectivity not established","Single lab"]},{"year":2016,"claim":"Linked ARL6IP5 to receptor abundance control by showing it downregulates HER2 via ERK/PEA3 transcriptional and c-Cbl degradation routes, suppressing migration.","evidence":"Migration assays, G-LISA, EMSA, reporter assays, and co-IP of c-Cbl/HER2","pmids":["27167206","27708243"],"confidence":"Medium","gaps":["Whether ARL6IP5 directly engages HER2 or its ligases unclear","Single lab"]},{"year":2017,"claim":"Showed ARL6IP5 suppresses TRAIL-induced apoptosis by directing MARCH8-mediated DR4 ubiquitination at K273.","evidence":"Overexpression/knockdown, site-specific ubiquitination, apoptosis assays, tissue correlation","pmids":["28671676"],"confidence":"Medium","gaps":["Direct ARL6IP5-MARCH8 interaction not demonstrated","Single lab"]},{"year":2017,"claim":"Revealed POMC as an ER cargo whose retention by ARL6IP5 limits α-MSH secretion and regulates feeding via melanocortin signaling.","evidence":"FRET interaction, KO mice, glucose tolerance, ICV antagonist infusion, serum α-MSH","pmids":["28904020"],"confidence":"Medium","gaps":["Cell-type specificity of the POMC interaction not resolved","Single lab"]},{"year":2018,"claim":"Identified RNF185 as the E3 ligase that ubiquitinates ARL6IP5 at K158 for proteasomal turnover, defining how ARL6IP5 levels are set.","evidence":"Co-IP, ubiquitination assay, K158 mutagenesis, tissue correlation, in vivo metastasis model","pmids":["29481911"],"confidence":"Medium","gaps":["Signals controlling RNF185 activity toward ARL6IP5 unknown","Single lab"]},{"year":2018,"claim":"Extended glutamate-transporter regulation to astrocytic GLT-1, showing ARL6IP5 supports GLT-1 expression via MAPK and PI3K/CREB signaling.","evidence":"Astrocyte-specific KO mice, GLT-1 assays, pathway inhibitors, CREB siRNA, neurotoxin PD models","pmids":["29500411"],"confidence":"Medium","gaps":["Direct vs signaling-mediated GLT-1 control not separated","Single lab"]},{"year":2018,"claim":"Demonstrated ARL6IP5 negatively regulates surface CXCR4 through proteasomal degradation to suppress invasion.","evidence":"Invasion assays, surface flow cytometry, proteasome inhibitor and CXCR4 rescue","pmids":["29658570"],"confidence":"Medium","gaps":["E3 ligase for CXCR4 not identified","Single lab"]},{"year":2021,"claim":"Refined HER2 regulation by identifying SMURF1-mediated ubiquitination at K716 controlled through a JAC1-NEDD4 axis.","evidence":"Site-specific ubiquitination, Western blot, in vitro/in vivo proliferation assays","pmids":["33875644"],"confidence":"Medium","gaps":["Direct ARL6IP5-SMURF1 binding not shown","Single lab"]},{"year":2022,"claim":"Connected ARL6IP5 to intestinal stem-cell biology through ERK/FBXW7-mediated NOTCH1 stability and the PPARγ/STAT5 axis.","evidence":"Jwa knockout mice, organoids, proteasome and pathway-inhibitor studies","pmids":["36147468"],"confidence":"Medium","gaps":["Direct molecular partner in NOTCH1 control unidentified","Single lab"]},{"year":2023,"claim":"Linked ARL6IP5 to autophagy induction and α-synuclein clearance by stabilizing free ATG12 and enhancing Rab1-dependent autophagosome formation.","evidence":"Overexpression/knockdown, autophagic flux, ATG12 ubiquitination, co-IP, cellular PD model","pmids":["37445677"],"confidence":"Medium","gaps":["Direct ATG12 binding not definitively shown","Single lab"]},{"year":2024,"claim":"Identified a neuroprotective ferroptosis mechanism whereby ARL6IP5 occupies the NCOA4 ferritin-binding site to block ferritinophagy.","evidence":"Molecular docking, co-IP, IF, genetic manipulation in cellular and animal PD models","pmids":["38744191"],"confidence":"Medium","gaps":["Structural validation of the docking model lacking","Single lab"]},{"year":2024,"claim":"Showed ARL6IP5 drives reticulophagy via Ca2+/AMPK and CALCOCO1/LAMP1 to reduce prion burden and ER stress, generalizing its ER-clearance role.","evidence":"Prion-infected cells, autophagic flux, co-IP (CALCOCO1, LAMP1), AMPK inhibition, Ca2+ measurement","pmids":["39394963"],"confidence":"Medium","gaps":["Relationship to FAM134B ER-phagy pathway not integrated","Single lab"]},{"year":2025,"claim":"Defined ARL6IP5 as a PRA1-domain ER membrane-shaping protein that constricts ER tubules and is required for FAM134B-mediated ER-phagy, providing a structural basis for its ER functions.","evidence":"Live-cell ER imaging, ER-phagy flux assay, domain mutagenesis, rescue with ARL6IP1, microtubule depolymerization","pmids":["40209949"],"confidence":"High","gaps":["High-resolution structure of the constriction mechanism lacking","Link between ER-shaping and cargo-retention functions not unified"]},{"year":null,"claim":"How the single ER membrane-shaping/cargo-retention activity of ARL6IP5 is reconciled with its reported nuclear DNA-repair and diverse cytoplasmic signaling functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model unifying the transmembrane and nuclear roles","Mechanism of regulated relocalization between ER and nucleus unknown","Direct vs indirect nature of many signaling effects undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[18]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,3,12,18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18,20,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,11,23,24]}],"complexes":[],"partners":["EAAC1","XRCC1","RAB1","POMC","RANKL","NCOA4","RNF185","CALCOCO1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75915","full_name":"PRA1 family protein 3","aliases":["ADP-ribosylation factor-like protein 6-interacting protein 5","ARL-6-interacting protein 5","Aip-5","Cytoskeleton-related vitamin A-responsive protein","Dermal papilla-derived protein 11","GTRAP3-18","Glutamate transporter EAAC1-interacting protein","JM5","Prenylated Rab acceptor protein 2","Protein JWa","Putative MAPK-activating protein PM27"],"length_aa":188,"mass_kda":21.6,"function":"Regulates intracellular concentrations of taurine and glutamate. Negatively modulates SLC1A1/EAAC1 glutamate transport activity by decreasing its affinity for glutamate in a PKC activity-dependent manner. Plays a role in the retention of SLC1A1/EAAC1 in the endoplasmic reticulum","subcellular_location":"Endoplasmic reticulum membrane; Cell membrane; Cytoplasm; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/O75915/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARL6IP5","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000144746","cell_line_id":"CID000502","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"ARPC2","stoichiometry":10.0},{"gene":"ARPC1B","stoichiometry":10.0},{"gene":"ARPC1A","stoichiometry":10.0},{"gene":"ACTR2","stoichiometry":10.0},{"gene":"YWHAG","stoichiometry":10.0},{"gene":"YWHAH","stoichiometry":10.0},{"gene":"LMNB2","stoichiometry":10.0},{"gene":"RTN4","stoichiometry":4.0},{"gene":"ARL6IP1","stoichiometry":0.2},{"gene":"YWHAB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000502","total_profiled":1310},"omim":[{"mim_id":"605709","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 6-INTERACTING PROTEIN 5; ARL6IP5","url":"https://www.omim.org/entry/605709"},{"mim_id":"300840","title":"PRA1 DOMAIN FAMILY, MEMBER 2; PRAF2","url":"https://www.omim.org/entry/300840"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARL6IP5"},"hgnc":{"alias_symbol":["PRAF3","JWA","GTRAP3-18","DERP11","HSPC127","Yip6b"],"prev_symbol":[]},"alphafold":{"accession":"O75915","domains":[{"cath_id":"-","chopping":"27-144","consensus_level":"high","plddt":93.4155,"start":27,"end":144},{"cath_id":"1.20.5","chopping":"158-188","consensus_level":"medium","plddt":86.1132,"start":158,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75915","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75915-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75915-F1-predicted_aligned_error_v6.png","plddt_mean":89.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARL6IP5","jax_strain_url":"https://www.jax.org/strain/search?query=ARL6IP5"},"sequence":{"accession":"O75915","fasta_url":"https://rest.uniprot.org/uniprotkb/O75915.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75915/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75915"}},"corpus_meta":[{"pmid":"11242046","id":"PMC_11242046","title":"Modulation 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35739964","citation_count":7,"is_preprint":false},{"pmid":"30881473","id":"PMC_30881473","title":"Jwa Kum Whan Attenuates Nonalcoholic Fatty Liver Disease by Modulating Glucose Metabolism and the Insulin Signaling Pathway.","date":"2019","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/30881473","citation_count":7,"is_preprint":false},{"pmid":"14761432","id":"PMC_14761432","title":"[Effect of differentiation inducer and heat stress on the expression of JWA protein and Hsp70 of K562 cells].","date":"2003","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/14761432","citation_count":7,"is_preprint":false},{"pmid":"23461062","id":"PMC_23461062","title":"Downregulation of JWA expression in human esophageal squamous cell carcinoma and its clinical significance.","date":"2012","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/23461062","citation_count":6,"is_preprint":false},{"pmid":"15033023","id":"PMC_15033023","title":"[Expressions of JWA protein and heat stress protein 70 induced by cell differentiation inducers combined with heat stress in K562 cells].","date":"2004","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/15033023","citation_count":6,"is_preprint":false},{"pmid":"36230577","id":"PMC_36230577","title":"Targeting JWA for Cancer Therapy: Functions, Mechanisms and Drug Discovery.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36230577","citation_count":5,"is_preprint":false},{"pmid":"16331563","id":"PMC_16331563","title":"[A case-control study on JWA promoter -76G-->C polymorphism and the susceptibility of bladder cancer].","date":"2005","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16331563","citation_count":5,"is_preprint":false},{"pmid":"14761492","id":"PMC_14761492","title":"[The mechanism of JWA gene involved in oxidative stress of cells].","date":"2003","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/14761492","citation_count":5,"is_preprint":false},{"pmid":"16701030","id":"PMC_16701030","title":"[The role of JWA in N-methyl-N'-nitro-N-nitrosoguanidine induced human bronchial epithelial cell apoptosis].","date":"2006","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/16701030","citation_count":5,"is_preprint":false},{"pmid":"17049984","id":"PMC_17049984","title":"Functional variations in the JWA gene are associated with increased odds of leukemias.","date":"2006","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/17049984","citation_count":5,"is_preprint":false},{"pmid":"24926382","id":"PMC_24926382","title":"JWA regulates human esophageal squamous cell carcinoma and human esophageal cells through different mitogen-activated protein kinase signaling pathways.","date":"2014","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24926382","citation_count":4,"is_preprint":false},{"pmid":"28904020","id":"PMC_28904020","title":"GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin.","date":"2017","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28904020","citation_count":3,"is_preprint":false},{"pmid":"26220341","id":"PMC_26220341","title":"Overexpression of Arl6ip5 in osteoblast regulates RANKL subcellualr localization.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26220341","citation_count":3,"is_preprint":false},{"pmid":"29392419","id":"PMC_29392419","title":"Hepatic glutamate transport and glutamine synthesis capacities are decreased in finished vs. growing beef steers, concomitant with increased GTRAP3-18 content.","date":"2018","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/29392419","citation_count":3,"is_preprint":false},{"pmid":"16105456","id":"PMC_16105456","title":"[Expression of novel environmental responsive protein JWA involved in the oxidative stress responsiveness in MCF-7 cells].","date":"2005","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/16105456","citation_count":3,"is_preprint":false},{"pmid":"15938853","id":"PMC_15938853","title":"[Relationship between JWA expression and DNA damage-repair in human embryonic lung cells by benzo(a) pyrene].","date":"2005","source":"Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]","url":"https://pubmed.ncbi.nlm.nih.gov/15938853","citation_count":3,"is_preprint":false},{"pmid":"15938852","id":"PMC_15938852","title":"[JWA gene acts as sensitive molecule responsive to oxidative stress and apoptosis in K562 cells].","date":"2005","source":"Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]","url":"https://pubmed.ncbi.nlm.nih.gov/15938852","citation_count":3,"is_preprint":false},{"pmid":"16277846","id":"PMC_16277846","title":"[JWA gene in regulating committed differentiation of HL-60 cells induced by ATRA, Ara-C and TPA].","date":"2005","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/16277846","citation_count":3,"is_preprint":false},{"pmid":"16701031","id":"PMC_16701031","title":"[Effects of hemin and thermal stress exposure on JWA expression].","date":"2006","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/16701031","citation_count":3,"is_preprint":false},{"pmid":"28763891","id":"PMC_28763891","title":"[Autophagy regulated by JWA influenced sensitivity of esophageal cancer to cisplatin].","date":"2017","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/28763891","citation_count":3,"is_preprint":false},{"pmid":"17479403","id":"PMC_17479403","title":"Single nucleotide polymorphism of the JWA gene is associated with risk of leukemia: a case-control study in a Chinese population.","date":"2007","source":"Journal of toxicology and environmental health. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/17479403","citation_count":3,"is_preprint":false},{"pmid":"32213241","id":"PMC_32213241","title":"Disruption of SSBs repair to combat platinum resistance via the JWA-targeted Pt(IV) prodrug conjugated with a wogonin derivative.","date":"2020","source":"Die Pharmazie","url":"https://pubmed.ncbi.nlm.nih.gov/32213241","citation_count":3,"is_preprint":false},{"pmid":"40209949","id":"PMC_40209949","title":"ADP ribosylation factor-like GTPase 6-interacting protein 5 (Arl6IP5) is an ER membrane-shaping protein that modulates ER-phagy.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40209949","citation_count":2,"is_preprint":false},{"pmid":"39394963","id":"PMC_39394963","title":"A novel ER stress regulator ARL6IP5 induces reticulophagy to ameliorate the prion burden.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39394963","citation_count":2,"is_preprint":false},{"pmid":"16277847","id":"PMC_16277847","title":"[Influence of Qingdai compound on expression of bcr/abl and JWA in K562 cells].","date":"2005","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/16277847","citation_count":2,"is_preprint":false},{"pmid":"22357531","id":"PMC_22357531","title":"[The relationship between single nucleotide polymorphisms of JWA gene and susceptibility to hypertension in workers exposed to heat stress].","date":"2011","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22357531","citation_count":2,"is_preprint":false},{"pmid":"40714583","id":"PMC_40714583","title":"JWA mediates oxidative stress to promote vascular endothelial repair in obstructive sleep apnea-hypopnea syndrome.","date":"2025","source":"Sleep medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40714583","citation_count":1,"is_preprint":false},{"pmid":"29545876","id":"PMC_29545876","title":"JWA deficiency induces malignant transformation of murine embryonic fibroblast cells.","date":"2018","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29545876","citation_count":1,"is_preprint":false},{"pmid":"24557627","id":"PMC_24557627","title":"Effects of hemin and thermal stress exposure on JWA expression.","date":"2007","source":"Frontiers of medicine in China","url":"https://pubmed.ncbi.nlm.nih.gov/24557627","citation_count":1,"is_preprint":false},{"pmid":"17908428","id":"PMC_17908428","title":"[The effect of PKC phosphorylation sites mutation in JWA coding region on TPA-induced MCF-7 cell differentiation].","date":"2007","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/17908428","citation_count":1,"is_preprint":false},{"pmid":"16640902","id":"PMC_16640902","title":"[Expression deficiency of JWA enhanced DNA damage and delayed DNA repair in HeLa cells induced by benzo (a) pyrene exposure].","date":"2006","source":"Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]","url":"https://pubmed.ncbi.nlm.nih.gov/16640902","citation_count":1,"is_preprint":false},{"pmid":"29872729","id":"PMC_29872729","title":"Rab1a rescues the toxicity of PRAF3.","date":"2018","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/29872729","citation_count":0,"is_preprint":false},{"pmid":"40503170","id":"PMC_40503170","title":"ADP ribosylation factor-like GTPase 6-interacting protein 5 (ARL6IP5): a prenylated Rab acceptor protein 1 (PRA1) family protein that shapes the ER membrane and regulates ER-phagy.","date":"2025","source":"Autophagy reports","url":"https://pubmed.ncbi.nlm.nih.gov/40503170","citation_count":0,"is_preprint":false},{"pmid":"40253526","id":"PMC_40253526","title":"ARL6IP5 in cancers: bidirectional function and therapeutic value.","date":"2025","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40253526","citation_count":0,"is_preprint":false},{"pmid":"19080375","id":"PMC_19080375","title":"[JWA regulates N-methyl-N'-nitro-N-nitrosoguanidine induced malignant transformation in human bronchial epithelial cells].","date":"2008","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19080375","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45569,"output_tokens":7788,"usd":0.126764,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17255,"output_tokens":6997,"usd":0.1306,"stage2_stop_reason":"end_turn"},"total_usd":0.257364,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"GTRAP3-18 (ARL6IP5) specifically interacts with the carboxy-terminal intracellular domain of EAAC1 (neuronal glutamate transporter), localizes to the cell membrane and cytoplasm, and increasing GTRAP3-18 expression reduces EAAC1-mediated glutamate transport by lowering substrate affinity.\",\n      \"method\": \"Co-immunoprecipitation, functional transport assay in cells, overexpression\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction mapping, functional transport assay, replicated by multiple subsequent labs\",\n      \"pmids\": [\"11242046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GTRAP3-18 is a resident endoplasmic reticulum protein that delays ER exit of EAAC1 and other excitatory amino acid transporter family members; it self-associates via hydrophobic domain interactions in the ER membrane and uses cytoplasmic C-terminal interactions to regulate trafficking.\",\n      \"method\": \"Subcellular fractionation, ER exit assay (VSVG transport), co-immunoprecipitation, domain deletion mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, trafficking assay, mutagenesis) in single study, consistent with independent reports\",\n      \"pmids\": [\"18167356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GTRAP3-18 at the plasma membrane negatively and dominantly regulates intracellular glutathione content by controlling EAAC1-mediated cysteine uptake; increasing cell-surface GTRAP3-18 (via methyl-β-cyclodextrin) decreases GSH, while decreasing it (via antisense oligonucleotides) increases GSH.\",\n      \"method\": \"Pharmacological manipulation of membrane GTRAP3-18 levels, antisense knockdown, GSH measurement, oxidative stress assay\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional manipulation (increase and decrease), replicated in vivo and in vitro across multiple papers\",\n      \"pmids\": [\"17646425\", \"18799673\", \"21373771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GTRAP3-18 acts as a negative regulator of Rab1, inhibiting ER-to-Golgi trafficking; overexpression reduces VSVG transport rate, slows cargo concentration of EAAC1 into transport complexes, and inhibits neurite outgrowth in CAD cells—effects rescued by Rab1 co-expression.\",\n      \"method\": \"VSVG transport assay, Brefeldin A treatment, neurite length measurement, rescue by Rab1 co-expression\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts, rescue experiment with Rab1 provides epistasis evidence\",\n      \"pmids\": [\"18363836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GTRAP3-18 interacts with EAAC1 at the plasma membrane and dominantly determines intracellular neuronal glutathione levels; genetic reduction of GTRAP3-18 in mouse brain increases plasma membrane EAAC1 and raises brain GSH, while overexpression suppresses GSH.\",\n      \"method\": \"Genetic manipulation (transgenic mice), co-immunoprecipitation, GSH measurement in primary neurons and mouse brain\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model plus in vitro co-IP, replicated in multiple subsequent studies\",\n      \"pmids\": [\"18799673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JWA interacts with XRCC1 and functions as a base excision repair protein for oxidative-stress-induced DNA single-strand breaks: JWA is translocated to the nucleus by XRCC1, co-localizes with XRCC1 foci after DNA damage, regulates XRCC1 transcriptionally via MAPK/E2F1, and protects XRCC1 from ubiquitination and proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, SSB repair assay (comet assay), ubiquitination assay, reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods establishing direct physical interaction, functional repair assay, and post-translational mechanism\",\n      \"pmids\": [\"19208635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JWA knockdown increases melanoma cell adhesion and invasion and promotes metastatic colony formation in vivo by intensifying integrin αVβ3 signaling through regulation of nuclear factor Sp1.\",\n      \"method\": \"siRNA knockdown, invasion/adhesion assays, in vivo metastasis model (B16-F10, A375), Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with pathway placement (integrin αVβ3/Sp1), single lab\",\n      \"pmids\": [\"19946336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JWA is required for rearrangement of F-actin cytoskeleton and activation of MAPK cascades (ERK, downstream FAK and COX-2) induced by As2O3 and PMA; JWA overexpression alone inhibits cancer cell migration, while JWA deficiency accelerates migration. SDR-SLR motifs of JWA are critical for MAPK cascade activation and cell migration.\",\n      \"method\": \"Overexpression and antisense knockdown, cell migration assay (wound healing/transwell), F-actin staining, MAPK phosphorylation western blot, domain mutagenesis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation plus domain mutagenesis, single lab\",\n      \"pmids\": [\"17336041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GTRAP3-18-deficient mice show increased EAAC1 expression at the plasma membrane, increased neuronal GSH content, and neuroprotection against oxidative stress, as well as improved motor/spatial learning and memory.\",\n      \"method\": \"Gene-targeting knockout mice, membrane fractionation, GSH measurement, behavioral testing, oxidative stress challenge\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal readouts, replicates prior pharmacological findings\",\n      \"pmids\": [\"22210510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JWA regulates cisplatin-induced DNA damage and apoptosis through the CK2-phospho-XRCC1-XRCC1 pathway: in normal cells JWA upregulates XRCC1, but in cisplatin-resistant gastric cancer cells JWA promotes XRCC1 degradation; mutation of CK2-targeted 518S/519T/523T residues of XRCC1 blocks this negative regulation.\",\n      \"method\": \"Site-directed mutagenesis of XRCC1 phosphorylation sites, Western blot, cell viability assay, cisplatin-resistant cell models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site mutagenesis identifies specific CK2-XRCC1 mechanism, single lab\",\n      \"pmids\": [\"25476899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"E3 ubiquitin ligase RNF185 directly interacts with JWA and promotes its ubiquitination at K158, leading to proteasomal degradation; RNF185 expression is negatively correlated with JWA in gastric cancer tissues.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K158), Western blot, in vivo metastasis model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and site-specific ubiquitination identified, single lab\",\n      \"pmids\": [\"29481911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JWA suppresses TRAIL-induced apoptosis in cisplatin-resistant gastric cancer cells by promoting ubiquitination of death receptor 4 (DR4) at K273 via upregulation of the E3 ubiquitin ligase MARCH8; JWA and DR4 protein levels are negatively correlated in gastric cancer tissues.\",\n      \"method\": \"Overexpression/knockdown, ubiquitination assay, site-directed mutagenesis (DR4 K273), Western blot, apoptosis assay\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific ubiquitination and E3 ligase identified, single lab\",\n      \"pmids\": [\"28671676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Arl6ip5 is expressed in osteoblasts and functions as an ER calcium regulator controlling calmodulin signaling for osteoblast proliferation; Arl6ip5 deficiency induces ER stress and ER stress-mediated apoptosis (via CHOP), impairs osteoblast differentiation, and increases RANKL expression to enhance osteoclastogenesis.\",\n      \"method\": \"Conditional knockout mice, calcium flux assay, ER stress markers (Western blot), siRNA knockdown, histomorphometry, in vitro osteoblast/osteoclast assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout plus multiple in vitro mechanistic readouts, single lab\",\n      \"pmids\": [\"25321471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Overexpression of Arl6ip5 in osteoblasts retains RANKL in the ER, decreases soluble RANKL secretion, and inhibits osteoclastogenesis; Arl6ip5 physically binds RANKL and disrupts the RANKL-OPG complex. Deletion of the NH2-terminal 1–36 amino acids of Arl6ip5 abolishes its interaction with RANKL and restores RANKL secretion.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutagenesis, conditioned medium RANKL ELISA, osteoclast formation assay, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding identified with deletion mutagenesis, functional consequence on RANKL trafficking, single lab\",\n      \"pmids\": [\"26220341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GTRAP3-18 interacts with pro-opiomelanocortin (POMC) in the ER, retaining it and reducing α-MSH secretion; GTRAP3-18-deficient mice show hypophagia, lean bodies, elevated α-MSH levels, and AMPK inhibition, effects reversed by melanocortin 4 receptor antagonist.\",\n      \"method\": \"FRET (fluorescence resonance energy transfer) interaction assay, GTRAP3-18-deficient mice, intraperitoneal glucose tolerance test, intracerebroventricular antagonist infusion, serum α-MSH measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET establishes direct interaction, KO mouse model with pharmacological rescue, single lab\",\n      \"pmids\": [\"28904020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Astrocytic JWA deficiency reduces expression of the glutamate transporter GLT-1 and glutamate uptake in vivo and in vitro; this occurs via suppression of MAPK and PI3K/CREB signaling. JWA-increased GLT-1 expression is abolished by MEK and PI3K inhibitors and by CREB silencing.\",\n      \"method\": \"Astrocyte-specific conditional JWA knockout mice, in vitro GLT-1 expression assay, pharmacological pathway inhibitors, CREB siRNA, MPTP/paraquat neurotoxin models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with pharmacological epistasis, single lab\",\n      \"pmids\": [\"29500411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JWA is required for chronic morphine-induced maintenance of delta opioid receptor (DOR) stability via the ubiquitin-proteasome pathway; JWA knockdown in rats reduces morphine withdrawal response and suppresses DOR expression as well as DARPP-32 and MAP kinase activation.\",\n      \"method\": \"siRNA knockdown in rats, in vitro chronic morphine cell model, Western blot, ubiquitin-proteasome pathway assay, behavioral withdrawal scoring\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown plus in vitro mechanistic follow-up identifying ubiquitin-proteasome pathway, single lab\",\n      \"pmids\": [\"21600884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JWA physically occupies the ferritin binding site of NCOA4 (nuclear receptor coactivator 4), thereby inhibiting NCOA4-mediated ferritinophagy and reducing iron-dependent ferroptosis in dopaminergic neurons; molecular docking, co-immunoprecipitation, and immunofluorescence confirm direct JWA-NCOA4 interaction.\",\n      \"method\": \"Molecular docking, co-immunoprecipitation, immunofluorescence, genetic manipulation (JWA overexpression/knockdown), cellular and animal PD models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods confirming direct interaction (docking + co-IP + IF), functional ferroptosis readout, single lab\",\n      \"pmids\": [\"38744191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARL6IP5 is an ER membrane-shaping protein containing the PRA1 domain; upon overexpression it induces extensive ER tubular networks and constricts the ER membrane (excluding luminal ER enzymes from tubules). ARL6IP5 knockdown impairs ER morphology and reduces FAM134B-mediated ER-phagy flux. Disruption of putative short hairpin structures in the PRA1 domain abolishes membrane constriction. ARL6IP5 and ARL6IP1 (an RHD-containing protein) can functionally substitute for each other in ER shaping.\",\n      \"method\": \"siRNA knockdown, overexpression, live-cell imaging of ER morphology, ER-phagy flux assay, domain mutagenesis, microtubule depolymerization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (live imaging, flux assay, domain mutagenesis, rescue experiments), defines novel ER membrane-shaping mechanism, single lab but rigorous\",\n      \"pmids\": [\"40209949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ARL6IP5 induces autophagy and reduces α-synuclein aggregate burden by stabilizing free ATG12 (preventing its ubiquitination and degradation) and enhancing Rab1-dependent autophagosome initiation and elongation.\",\n      \"method\": \"ARL6IP5 overexpression/knockdown, autophagic flux assay, ATG12 ubiquitination assay, co-immunoprecipitation, cellular PD model (A53T α-synuclein)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mechanistic interaction (ATG12 stabilization, Rab1-dependence) with functional autophagy readout, single lab\",\n      \"pmids\": [\"37445677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ARL6IP5 induces reticulophagy to reduce PrPSc burden and alleviate ER stress; ARL6IP5-induced reticulophagy depends on Ca2+-mediated AMPK activation and involves physical interaction with reticulophagy receptor CALCOCO1 and lysosomal marker LAMP1 for lysosomal degradation.\",\n      \"method\": \"Overexpression/knockdown in prion-infected cells (RML-ScN2a), autophagic flux assay, co-immunoprecipitation (CALCOCO1, LAMP1), AMPK inhibition, Ca2+ measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction with CALCOCO1 identified, Ca2+/AMPK pathway established, single lab\",\n      \"pmids\": [\"39394963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab1a can rescue the cytotoxicity caused by PRAF3 (ARL6IP5) overexpression, presumably by positively regulating ER-to-Golgi trafficking and counteracting the negative modulation by PRAF3.\",\n      \"method\": \"Co-expression rescue assay, cell viability assay\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single rescue assay, no direct binding confirmed in this paper, mechanism inferred\",\n      \"pmids\": [\"29872729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"JWA suppresses EGF-induced cell migration and actin cytoskeletal rearrangement in HER2-overexpressing gastric cancer cells by downregulating HER2 expression through ERK activation and consequent PEA3 upregulation; modulation of HER2 by JWA is ERK/PEA3-dependent.\",\n      \"method\": \"Transwell migration assay, G-LISA (Rho GTPase activity), Western blot, real-time PCR, EMSA, luciferase reporter assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods establishing ERK/PEA3 pathway for HER2 regulation, single lab\",\n      \"pmids\": [\"27167206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"JWA promotes HER2 degradation via the E3 ubiquitin ligase c-Cbl, representing a mechanism for JWA-induced HER2 downregulation that confers lapatinib resistance while reversing cisplatin resistance in gastric cancer cells.\",\n      \"method\": \"Western blot, co-immunoprecipitation (c-Cbl/HER2), overexpression/knockdown, cell viability assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP identifies c-Cbl as the degradation mechanism, replicated across two JWA/HER2 pathway papers\",\n      \"pmids\": [\"27708243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JWA suppresses HER2 ubiquitination and proliferation of HER2-positive breast cancer through the E3 ubiquitin ligase SMURF1 (increased by JAC1-mediated decrease of NEDD4, the E3 ligase for SMURF1); JWA promotes HER2 ubiquitination at K716 via SMURF1.\",\n      \"method\": \"Ubiquitination assay (K716 site), Western blot, overexpression, in vitro and in vivo proliferation assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific ubiquitination (K716) and E3 ligase (SMURF1) identified, single lab\",\n      \"pmids\": [\"33875644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JWA suppresses breast cancer cell invasion by negatively regulating cell-surface CXCR4 expression via proteasome-mediated degradation (not transcriptional inhibition); normalizing CXCR4 reverses JWA's inhibitory effect on invasion.\",\n      \"method\": \"Overexpression/knockdown, invasion assay, flow cytometry (surface CXCR4), proteasome inhibitor rescue, CXCR4 rescue experiment\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteasome dependence established, CXCR4 rescue provides functional epistasis, single lab\",\n      \"pmids\": [\"29658570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JWA deficiency promotes NOTCH1 degradation via the ERK/FBXW7-mediated ubiquitin-proteasome pathway, thus disturbing the PPARγ/STAT5 axis and reducing intestinal stem cell function and epithelial cell lineage distribution.\",\n      \"method\": \"Jwa knockout mice, intestinal organoids, Western blot, proteasome assay, pathway inhibitor studies\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with defined pathway (ERK/FBXW7/NOTCH1), single lab\",\n      \"pmids\": [\"36147468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JWA negatively regulates CD44 expression in lung cancer by inhibiting ubiquitination-mediated degradation of SP1 (Specificity Protein 1); nicotine downregulates JWA via the CHRNA5-mediated AKT pathway, leading to elevated SP1 and CD44.\",\n      \"method\": \"Western blot, ubiquitination assay, in vivo xenograft, siRNA/overexpression, pharmacological AKT pathway inhibition\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination mechanism and upstream CHRNA5/AKT pathway identified, in vivo validation, single lab\",\n      \"pmids\": [\"37224781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JAC4 promotes NEDD4L stability via AMPK-mediated phosphorylation at Thr367; the WW domain of NEDD4L (E3 ubiquitin ligase) interacts with EGFR and promotes its ubiquitination at K716, leading to EGFR degradation; this cascade is initiated by JAC4 directly binding CTBP1 and blocking its nuclear translocation, thereby de-repressing JWA gene transcription.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K716), mass spectrometry, cellular thermal shift assay, molecular docking, qRT-PCR, in vivo xenograft\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple interactions identified (JAC4-CTBP1, AMPK-NEDD4L, NEDD4L-EGFR K716), single lab but several orthogonal methods\",\n      \"pmids\": [\"37240137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAC1 specifically binds YY1 and eliminates its transcriptional repression of the JWA gene; JAC1 also promotes ubiquitination and degradation of YY1, and disrupts the YY1-HSF1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, luciferase reporter assay, Western blot\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and ubiquitination of YY1 identified with multiple methods, single lab\",\n      \"pmids\": [\"35383155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"JWA knockdown attenuates arsenic trioxide (As2O3)-induced apoptosis in HeLa and MCF-7 cells; JWA is required for As2O3-induced mitochondrial transmembrane potential loss, caspase-9 activation, and MEK1/2, ERK1/2, and JNK phosphorylations. JWA expression is induced by intracellular ROS generated by As2O3.\",\n      \"method\": \"siRNA knockdown, apoptosis assay (caspase activity, mitochondrial membrane potential), MAPK phosphorylation western blot, ROS measurement\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined pro-apoptotic pathway placement via knockdown, single lab\",\n      \"pmids\": [\"18387645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JWA deficiency in neurons (JWA-nKO mice) enhances neurogenesis (survival/migration of newborn neurons and neurite growth) and lowers the LTP threshold in hippocampal dentate gyrus via the FAK-PI3K-Akt-mTOR pathway; PI3K or FAK inhibition abolishes enhanced neurogenesis and LTP; telomerase inhibition suppresses both neurogenesis and LTP enhancement.\",\n      \"method\": \"Neuronal-specific JWA knockout mice, Morris water maze, LTP electrophysiology, BrdU labeling, pharmacological inhibitor epistasis (PI3K, FAK, mTOR), telomerase inhibitor\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with pharmacological epistasis defining FAK/PI3K/Akt/mTOR pathway, single lab\",\n      \"pmids\": [\"25432888\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARL6IP5/GTRAP3-18/JWA is a four-transmembrane PRA1-domain ER-resident protein that (1) retains and inhibits the neuronal glutamate/cysteine transporter EAAC1 in the ER, reducing its plasma membrane expression and thereby suppressing neuronal glutathione synthesis; (2) negatively regulates Rab1-dependent ER-to-Golgi trafficking and acts as an ER membrane-shaping protein whose PRA1 domain constricts ER tubules and is required for FAM134B-mediated ER-phagy; (3) interacts with POMC in the ER to regulate α-MSH secretion and food intake; (4) in the nucleus/cytoplasm functions as a scaffold for DNA base excision repair by multi-interacting with XRCC1 (protecting it from ubiquitination and transcriptionally upregulating it via MAPK/E2F1), while being itself ubiquitinated at K158 by RNF185 for proteasomal degradation; (5) modulates cell migration and actin cytoskeletal rearrangement via MAPK cascades (ERK/FAK/COX-2) and integrin αVβ3/Sp1 signaling; (6) regulates HER2 levels through ERK/PEA3 and c-Cbl-mediated ubiquitination, and promotes DR4 ubiquitination at K273 via MARCH8 to suppress TRAIL-induced apoptosis; and (7) protects dopaminergic neurons by binding the ferritin-binding site of NCOA4 to inhibit ferritinophagy and ferroptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARL6IP5 (GTRAP3-18/JWA/PRAF3) is a four-transmembrane PRA1-domain endoplasmic reticulum protein that governs the ER residence and surface delivery of membrane transporters and acts more broadly as an ER membrane-shaping factor [#1, #18]. Its founding function is to bind the C-terminal intracellular domain of the neuronal glutamate/cysteine transporter EAAC1, retaining it in the ER and lowering its substrate affinity, thereby restricting EAAC1-mediated cysteine uptake and dominantly suppressing intracellular glutathione synthesis [#0, #1, #2]; loss of ARL6IP5 in mice raises plasma-membrane EAAC1, elevates neuronal GSH, and confers neuroprotection against oxidative stress [#4, #8]. This trafficking control reflects a general role as a negative regulator of Rab1-dependent ER-to-Golgi transport, an activity rescued by Rab1 co-expression [#3, #21]. Through its PRA1 domain ARL6IP5 constricts ER tubules and shapes the tubular ER network, and is required for FAM134B-mediated ER-phagy [#18]; consistent with a reticulophagy role, it promotes autophagy/ER-phagy via Ca2+/AMPK signaling and interaction with CALCOCO1 to clear pathological aggregates [#20]. The protein also retains other secretory cargos in the ER, including POMC—limiting α-MSH secretion to influence food intake [#14]—and RANKL, decreasing soluble RANKL and inhibiting osteoclastogenesis [#13], while controlling ER calcium and CHOP-dependent ER stress in osteoblasts [#12]. In a distinct nuclear/cytoplasmic role, ARL6IP5 (as JWA) functions in DNA single-strand-break base excision repair by interacting with XRCC1, being shuttled to the nucleus by XRCC1, transcriptionally upregulating XRCC1 via MAPK/E2F1, and protecting it from ubiquitin-proteasomal degradation [#5]. ARL6IP5 protein levels are themselves controlled by RNF185-mediated ubiquitination at K158 [#10]. Acting through MAPK cascades (ERK/FAK/COX-2) and integrin αVβ3/Sp1 signaling, it restrains cancer cell migration, adhesion, and invasion [#6, #7], and modulates the abundance of multiple receptors and death-pathway components by directing E3-ligase–dependent ubiquitination—promoting HER2 degradation via c-Cbl and SMURF1, and DR4 degradation via MARCH8 to suppress TRAIL-induced apoptosis [#11, #23, #24]. It additionally protects dopaminergic neurons by occupying the ferritin-binding site of NCOA4 to inhibit ferritinophagy and ferroptosis [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the first molecular function of ARL6IP5 by identifying it as a direct binding partner that down-regulates a neuronal glutamate transporter, answering what protein controls EAAC1 activity.\",\n      \"evidence\": \"Co-immunoprecipitation and functional transport assays with EAAC1 in cells\",\n      \"pmids\": [\"11242046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the subcellular site of inhibition\", \"Stoichiometry and structural basis of the EAAC1 interaction unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined ARL6IP5 as an ER-resident protein that delays ER exit of EAAC1, linking the inhibitory interaction to retention/trafficking rather than direct catalytic interference.\",\n      \"evidence\": \"Subcellular fractionation, VSVG ER exit assay, co-IP, and domain-deletion mutagenesis\",\n      \"pmids\": [\"18167356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how self-association is regulated\", \"Mechanism linking retention to transport affinity change unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed ARL6IP5 dominantly sets intracellular glutathione by controlling EAAC1-mediated cysteine uptake, connecting its trafficking role to redox homeostasis.\",\n      \"evidence\": \"Bidirectional pharmacological/antisense manipulation of GTRAP3-18 with GSH and oxidative-stress assays\",\n      \"pmids\": [\"17646425\", \"18799673\", \"21373771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate plasma-membrane from ER pools of the protein mechanistically\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified ARL6IP5 as a negative regulator of Rab1, broadening its role from EAAC1-specific retention to general ER-to-Golgi trafficking control.\",\n      \"evidence\": \"VSVG transport and neurite outgrowth assays rescued by Rab1 co-expression in CAD cells\",\n      \"pmids\": [\"18363836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not demonstrate direct ARL6IP5-Rab1 binding\", \"Did not define the GEF/GAP relationship to Rab1\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Confirmed in vivo that ARL6IP5 dosage controls brain glutathione via plasma-membrane EAAC1, validating the redox role genetically.\",\n      \"evidence\": \"Transgenic mouse manipulation, co-IP, and GSH measurement in neurons and brain\",\n      \"pmids\": [\"18799673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Behavioral/disease consequences not yet tested in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a nuclear/cytoplasmic moonlighting function in DNA repair, showing ARL6IP5 (JWA) scaffolds and stabilizes XRCC1 for base excision repair of oxidative single-strand breaks.\",\n      \"evidence\": \"Co-IP, IF co-localization, comet SSB-repair assay, ubiquitination and reporter assays\",\n      \"pmids\": [\"19208635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an ER transmembrane protein accesses the nucleus mechanistically not resolved\", \"Direct vs indirect XRCC1 protection not fully distinguished\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed ARL6IP5 upstream of MAPK-driven actin remodeling and cell migration, identifying motif requirements (SDR-SLR) for this signaling.\",\n      \"evidence\": \"Bidirectional manipulation, migration assays, F-actin staining, MAPK phospho-blots, domain mutagenesis\",\n      \"pmids\": [\"17336041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct upstream receptor link not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected the migration-suppressive function to anti-metastatic activity via integrin αVβ3/Sp1 signaling.\",\n      \"evidence\": \"siRNA, invasion/adhesion assays, in vivo melanoma metastasis model\",\n      \"pmids\": [\"19946336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target between JWA and integrin signaling unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that ARL6IP5 knockout improves neuronal antioxidant capacity and cognition, establishing physiological relevance of the EAAC1/GSH axis.\",\n      \"evidence\": \"Gene-targeted knockout mice with fractionation, GSH, behavioral and oxidative-stress readouts\",\n      \"pmids\": [\"22210510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address non-neuronal roles of the protein\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended ARL6IP5's receptor-stability role to delta opioid receptor maintenance during chronic morphine, implicating ubiquitin-proteasome control.\",\n      \"evidence\": \"siRNA knockdown in rats, chronic morphine cell model, ubiquitin-proteasome assays, behavioral withdrawal scoring\",\n      \"pmids\": [\"21600884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct E3 ligase not identified\", \"Mechanism of DOR stabilization not molecularly resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established ARL6IP5 as an ER calcium/calmodulin regulator in osteoblasts whose loss triggers CHOP-dependent ER stress and apoptosis.\",\n      \"evidence\": \"Conditional knockout mice, calcium flux, ER stress markers, histomorphometry, in vitro osteoblast/osteoclast assays\",\n      \"pmids\": [\"25321471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between ARL6IP5 and ER Ca2+ handling not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed ARL6IP5 modulates the CK2-phospho-XRCC1 axis context-dependently, switching from XRCC1 stabilization to degradation in cisplatin-resistant cells.\",\n      \"evidence\": \"Site-directed mutagenesis of XRCC1 CK2 sites, viability assays, resistant cell models\",\n      \"pmids\": [\"25476899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of the context-dependent switch unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated neuronal ARL6IP5 loss enhances neurogenesis and lowers LTP threshold via a FAK-PI3K-Akt-mTOR pathway.\",\n      \"evidence\": \"Neuron-specific knockout mice with behavioral, LTP, BrdU, and pharmacological epistasis\",\n      \"pmids\": [\"25432888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target initiating FAK/PI3K signaling unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified RANKL as an ER cargo retained by ARL6IP5, with an N-terminal (1-36) interaction controlling RANKL secretion and osteoclastogenesis.\",\n      \"evidence\": \"Co-IP, domain-deletion mutagenesis, RANKL ELISA, osteoclast formation assay\",\n      \"pmids\": [\"26220341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of cargo selectivity not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked ARL6IP5 to receptor abundance control by showing it downregulates HER2 via ERK/PEA3 transcriptional and c-Cbl degradation routes, suppressing migration.\",\n      \"evidence\": \"Migration assays, G-LISA, EMSA, reporter assays, and co-IP of c-Cbl/HER2\",\n      \"pmids\": [\"27167206\", \"27708243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ARL6IP5 directly engages HER2 or its ligases unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed ARL6IP5 suppresses TRAIL-induced apoptosis by directing MARCH8-mediated DR4 ubiquitination at K273.\",\n      \"evidence\": \"Overexpression/knockdown, site-specific ubiquitination, apoptosis assays, tissue correlation\",\n      \"pmids\": [\"28671676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ARL6IP5-MARCH8 interaction not demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed POMC as an ER cargo whose retention by ARL6IP5 limits α-MSH secretion and regulates feeding via melanocortin signaling.\",\n      \"evidence\": \"FRET interaction, KO mice, glucose tolerance, ICV antagonist infusion, serum α-MSH\",\n      \"pmids\": [\"28904020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type specificity of the POMC interaction not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified RNF185 as the E3 ligase that ubiquitinates ARL6IP5 at K158 for proteasomal turnover, defining how ARL6IP5 levels are set.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, K158 mutagenesis, tissue correlation, in vivo metastasis model\",\n      \"pmids\": [\"29481911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals controlling RNF185 activity toward ARL6IP5 unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended glutamate-transporter regulation to astrocytic GLT-1, showing ARL6IP5 supports GLT-1 expression via MAPK and PI3K/CREB signaling.\",\n      \"evidence\": \"Astrocyte-specific KO mice, GLT-1 assays, pathway inhibitors, CREB siRNA, neurotoxin PD models\",\n      \"pmids\": [\"29500411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs signaling-mediated GLT-1 control not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated ARL6IP5 negatively regulates surface CXCR4 through proteasomal degradation to suppress invasion.\",\n      \"evidence\": \"Invasion assays, surface flow cytometry, proteasome inhibitor and CXCR4 rescue\",\n      \"pmids\": [\"29658570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase for CXCR4 not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined HER2 regulation by identifying SMURF1-mediated ubiquitination at K716 controlled through a JAC1-NEDD4 axis.\",\n      \"evidence\": \"Site-specific ubiquitination, Western blot, in vitro/in vivo proliferation assays\",\n      \"pmids\": [\"33875644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ARL6IP5-SMURF1 binding not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected ARL6IP5 to intestinal stem-cell biology through ERK/FBXW7-mediated NOTCH1 stability and the PPARγ/STAT5 axis.\",\n      \"evidence\": \"Jwa knockout mice, organoids, proteasome and pathway-inhibitor studies\",\n      \"pmids\": [\"36147468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular partner in NOTCH1 control unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked ARL6IP5 to autophagy induction and α-synuclein clearance by stabilizing free ATG12 and enhancing Rab1-dependent autophagosome formation.\",\n      \"evidence\": \"Overexpression/knockdown, autophagic flux, ATG12 ubiquitination, co-IP, cellular PD model\",\n      \"pmids\": [\"37445677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ATG12 binding not definitively shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a neuroprotective ferroptosis mechanism whereby ARL6IP5 occupies the NCOA4 ferritin-binding site to block ferritinophagy.\",\n      \"evidence\": \"Molecular docking, co-IP, IF, genetic manipulation in cellular and animal PD models\",\n      \"pmids\": [\"38744191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural validation of the docking model lacking\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed ARL6IP5 drives reticulophagy via Ca2+/AMPK and CALCOCO1/LAMP1 to reduce prion burden and ER stress, generalizing its ER-clearance role.\",\n      \"evidence\": \"Prion-infected cells, autophagic flux, co-IP (CALCOCO1, LAMP1), AMPK inhibition, Ca2+ measurement\",\n      \"pmids\": [\"39394963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship to FAM134B ER-phagy pathway not integrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined ARL6IP5 as a PRA1-domain ER membrane-shaping protein that constricts ER tubules and is required for FAM134B-mediated ER-phagy, providing a structural basis for its ER functions.\",\n      \"evidence\": \"Live-cell ER imaging, ER-phagy flux assay, domain mutagenesis, rescue with ARL6IP1, microtubule depolymerization\",\n      \"pmids\": [\"40209949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the constriction mechanism lacking\", \"Link between ER-shaping and cargo-retention functions not unified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the single ER membrane-shaping/cargo-retention activity of ARL6IP5 is reconciled with its reported nuclear DNA-repair and diverse cytoplasmic signaling functions remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model unifying the transmembrane and nuclear roles\", \"Mechanism of regulated relocalization between ER and nucleus unknown\", \"Direct vs indirect nature of many signaling effects undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 3, 12, 18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18, 20, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 11, 23, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EAAC1\", \"XRCC1\", \"Rab1\", \"POMC\", \"RANKL\", \"NCOA4\", \"RNF185\", \"CALCOCO1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}