{"gene":"RAB37","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2000,"finding":"Rab37 is a novel Rab GTPase specifically expressed in mast cells (MC-9 line and bone marrow mast cells) and localizes to secretory granules, as shown by GFP-tagged Rab37 expression in bone marrow mast cells.","method":"GFP-tagging and fluorescence microscopy in bone marrow mast cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with functional implication, single lab but clear subcellular localization result","pmids":["10722846"],"is_preprint":false},{"year":2011,"finding":"Rab37 controls TNF-α secretion from activated macrophages; overexpression of wild-type or constitutively active Rab37 increases TNF-α secretion while siRNA knockdown decreases it. Rab37 interacts with Munc13-1, and TNF-α-containing vesicles co-localize with both Rab37 and Munc13-1.","method":"Overexpression/knockdown (siRNA), LC-MS/MS interactome, immunocytochemistry co-localization in RAW264.7 macrophages","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (overexpression, knockdown, MS, co-localization), single lab","pmids":["21805469"],"is_preprint":false},{"year":2011,"finding":"Rab37 is identified as a MetAP-2-specific substrate; aberrant accumulation of Rab37 (when N-terminal methionine excision is blocked by MetAP-2 inhibitor TNP-470) disrupts Wnt planar cell polarity (PCP) signaling. A Rab37 point mutant resistant to NME phenocopies MetAP-2 inhibition on Wnt PCP-dependent processes.","method":"MetAP-2 inhibitor treatment, NME-resistant Rab37 point mutant expression, functional PCP signaling assays","journal":"Chemistry & biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus functional rescue/phenocopy, single lab, two orthogonal approaches","pmids":["22035799"],"is_preprint":false},{"year":2013,"finding":"Rab37 localizes to insulin-containing large dense core granules in pancreatic β-cells, and its knockdown by RNAi impairs glucose-induced insulin secretion and reduces granule docking at the plasma membrane. Pull-down experiments show Rab37 does not interact with known Rab3a or Rab27a effectors, indicating it operates through a distinct mechanism.","method":"Confocal microscopy localization, RNAi knockdown with secretion assay, pull-down experiments in β-cell lines and human islets","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (localization, KD, pulldown), single lab","pmids":["23826383"],"is_preprint":false},{"year":2014,"finding":"RAB37 directly targets TIMP1 as a secretory cargo and regulates TIMP1 exocytosis in a nucleotide-dependent (GTP-dependent) manner; secreted TIMP1 inactivates MMP9 to suppress cancer cell migration in vitro and in vivo. Dysfunction of RAB37 abrogates metastasis suppression.","method":"Secretomics, cell migration/invasion assays, animal (tail-vein injection) metastasis models, nucleotide-binding mutant analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (secretomics, in vitro assays, in vivo mouse models, mutant analysis), replicated across subsequent studies","pmids":["25183545"],"is_preprint":false},{"year":2016,"finding":"In mast cells, Rab37 acts as a negative regulator of degranulation by interacting with Munc13-4 in a GTP-independent manner, forming a Rab27-Munc13-4-Rab37 complex that counteracts the vesicle-priming activity of the Rab27-Munc13-4 system. Knockdown of Rab37 or overexpression of dominant-active Rab37 both enhance degranulation; the hypersecretion phenotype in Rab37-knockdown cells is suppressed by simultaneous knockdown of Rab27a/b or Munc13-4.","method":"siRNA knockdown, dominant-active mutant overexpression, genetic epistasis (double knockdown), immunoprecipitation in RBL-2H3 mast cells","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis, Co-IP, multiple loss-of-function experiments with defined phenotypic readout, single lab but multiple orthogonal methods","pmids":["26931073"],"is_preprint":false},{"year":2016,"finding":"Rab37-mediated exocytosis of thrombospondin-1 (TSP1) from cancer cells inhibits angiogenesis and suppresses metastasis; secreted TSP1 inhibits p-FAK/p-paxillin/p-ERK migration signaling in both cancer epithelial cells and surrounding endothelial cells. Dysfunction of Rab37 or loss of TSP1 abolishes these suppressive effects.","method":"Cell migration/invasion, angiogenesis, and in vivo metastasis assays; conditioned medium experiments; signaling pathway analysis in ESCC cells","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (in vitro and in vivo), single lab","pmids":["28151721"],"is_preprint":false},{"year":2017,"finding":"RAB37 directly binds ATG5 and promotes autophagosome formation by recruiting ATG5-12 to the isolation membrane and facilitating assembly of the ATG5-ATG12-ATG16L1 complex. GTP-bound RAB37 shows enhanced interaction with ATG5-12, while GDP-stabilized mutation impairs the interaction. RAB37 promotes ATG5-12 interaction with ATG16L1, facilitating LC3B lipidation in a GTP-dependent manner.","method":"Direct binding assay, mutation analysis (GTP/GDP-binding mutants), Co-IP, isolation membrane localization, autophagy flux assays, knockdown and overexpression","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding demonstrated, mutagenesis, multiple orthogonal methods (Co-IP, localization, functional assays), replicated in subsequent autophagy papers","pmids":["29229996"],"is_preprint":false},{"year":2017,"finding":"PKCα phosphorylates Rab37 at threonine 172 (T172), leading to attenuation of its GTP-bound state, impairment of Rab37-mediated TIMP1 exocytosis, and reduction of metastasis suppression. Phospho-mimetic T172D mutant of Rab37 promotes tumor metastasis in vivo. PKCα reduces vesicle co-localization of Rab37 and TIMP1.","method":"In vitro kinase assay (PKCα phosphorylation of Rab37), site-directed mutagenesis (T172D phospho-mimetic), vesicle co-localization by confocal microscopy, in vivo metastasis assay","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, mutagenesis, in vivo validation, single lab but multiple orthogonal methods","pmids":["29312551"],"is_preprint":false},{"year":2018,"finding":"Rab37 mediates exocytosis of secreted frizzled-related protein-1 (SFRP1), an extracellular Wnt antagonist, to suppress Wnt signaling and cancer stemness in vitro and in vivo. Reconstitution experiments show SFRP1 secretion is crucial for Rab37-mediated cancer stemness suppression.","method":"Reconstitution experiments, SFRP1 recombinant protein treatment, xenograft tumor initiation assay, signaling pathway analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstitution and in vivo experiments, single lab","pmids":["30158579"],"is_preprint":false},{"year":2018,"finding":"VAMP8 (a v-SNARE) interacts with RAB37 and is required for TIMP1 exocytosis. VAMP8 co-localizes with RAB37 and facilitates trafficking of RAB37-TIMP1 vesicles. Reconstitution experiments (tail-vein injection, lung-to-lung metastasis) demonstrate VAMP8 is essential for RAB37-regulated vesicle trafficking of TIMP1 to suppress cancer metastasis.","method":"Confocal and TIRF microscopy, Co-IP, in vivo reconstitution assays (tail-vein injection, lung-to-lung metastasis mouse model)","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, live-cell imaging, in vivo reconstitution, single lab","pmids":["30165196"],"is_preprint":false},{"year":2018,"finding":"Rab37 mediates secretion of soluble ST2 (sST2) from lung cancer cells in a GTP-dependent manner, and secreted sST2 skews macrophage polarization toward anti-tumoral M1-like phenotype both in vitro and in xenografts.","method":"Overexpression/knockdown system, GTP/GDP mutant analysis, macrophage polarization assays, xenograft tumor model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTP-dependent mutant analysis, in vitro and in vivo functional assays, single lab","pmids":["29717487"],"is_preprint":false},{"year":2018,"finding":"RAB37 co-localizes with TIMP2 and regulates TIMP2 secretion in nasopharyngeal carcinoma cells, thereby inhibiting MMP2 activity and suppressing cell metastasis. RAB37 downregulation is attributed to hypermethylation of its promoter.","method":"Co-localization assay, secretion assay, MMP2 activity assay, ectopic overexpression and in vivo validation","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (co-localization, secretion, enzymatic activity), single lab","pmids":["30131385"],"is_preprint":false},{"year":2020,"finding":"RAB37 phosphorylation by PKCα (via the miR-200b/PKCα axis) is promoted by methionine treatment in gastric cancer stem cells, inactivating RAB37 and suppressing RAB37-mediated autophagy. Methionine also enhances RAB37 methylation. Methionine lyase (Metase) treatment reduces RAB37 phosphorylation and methylation, restoring autophagy.","method":"Lentiviral expression of methionine lyase, miR-200b/PKCα pathway analysis, methylation and phosphorylation assays, autophagy measurement in GCSCs","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (phosphorylation, methylation, autophagy flux), in vivo tumor model, single lab","pmids":["32926650"],"is_preprint":false},{"year":2021,"finding":"Rab37 in macrophages regulates IL-6 secretion in a GTPase-dependent manner, promoting M2 macrophage polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. These mechanisms were demonstrated using vesicle isolation, imaging, and chromatin immunoprecipitation showing STAT3 binding to the PD-1 promoter.","method":"Vesicle isolation, imaging analyses, ChIP assay for STAT3 binding at PD-1 promoter, Rab37 knockout mice syngeneic allograft, GTP/GDP mutant analysis","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (vesicle isolation, imaging, ChIP, KO mouse model), mechanistic pathway established","pmids":["34093869"],"is_preprint":false},{"year":2021,"finding":"RAB37 promotes adipogenic differentiation of hADSCs via TIMP1 secretion; RAB37 directly interacts with TIMP1 (shown by proximity ligation assay), and secreted TIMP1 signals through CD63/integrin β1 to promote FAK phosphorylation (Tyr397). Knockdown of TIMP1, CD63, or FAK inhibition impedes RAB37-mediated adipogenesis.","method":"Proximity ligation assay (direct interaction), cytokine array, ELISA, knockdown experiments, FAK phosphorylation assays in hADSCs","journal":"Stem cells international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proximity ligation assay for interaction, multiple knockdown experiments, single lab","pmids":["34858503"],"is_preprint":false},{"year":2022,"finding":"Rab37 mediates CHI3L1 (chitinase 3-like-1) intracellular vesicle trafficking and exocytosis in T cells and macrophages in a GTP-dependent manner; this is abolished in Rab37 knockout mice splenocytes and BMDMs, and attenuated with inactive GDP-bound Rab37. Secreted CHI3L1 activates AKT, β-catenin, and NF-κB signaling in cancer cells and macrophages.","method":"Vesicle isolation, TIRF microscopy, real-time confocal microscopy, Rab37 knockout mouse splenocytes/BMDMs, GTP/GDP mutant analysis","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (vesicle isolation, TIRF, confocal, KO mouse), GTP-dependence validated with mutants","pmids":["34987649"],"is_preprint":false},{"year":2022,"finding":"Secretory autophagy promotes RAB37-mediated TIMP1 exocytosis in a RAB37- and Sec22b-dependent manner. Knockdown of Atg5 or Atg7 in cells harboring active RAB37 decreases autophagy and TIMP1 secretion. RAB37 and Sec22b proteins were identified in purified autophagosomes. Sec22b (a SNARE) participates in vesicle/membrane fusion of secretory autophagy.","method":"Autophagosome purification (mass spec identification of RAB37 and Sec22b), immunoblotting, TEM, immunofluorescence, siRNA knockdown of ATG5/ATG7/Sec22b, lung-to-lung metastasis mouse model","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — autophagosome purification with biochemical identification, multiple gene knockdowns, in vivo validation, single lab but multiple orthogonal methods","pmids":["36457117"],"is_preprint":false},{"year":2023,"finding":"Starvation-activated RAB37 simultaneously drives autophagy activation and TIMP1 secretion via secretory autophagy in a Sec22b-dependent manner. Active GTP-bound RAB37 increases LC3-II levels and TIMP1 secretion; knockdown of Sec22b decreases TIMP1 secretion without affecting proliferation.","method":"Overexpression/knockdown system, LC3-II immunoblotting, motility assays, lung-to-lung mouse metastasis model, Sec22b siRNA","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo assays, mechanistic confirmation with Sec22b knockdown, single lab","pmids":["37151129"],"is_preprint":false},{"year":2023,"finding":"Rab37 directly binds Hsp90α and TIMP1 in ADSCs (shown by proximity ligation assay), regulates their secretion, and promotes ADSC proliferation, migration, and endothelial differentiation. Knockdown of Hsp90α or TIMP1 compromises Rab37's promoting effects.","method":"Proximity ligation assay, LC-MS/MS of conditioned media, ELISA, knockdown experiments, in vivo diabetic wound healing model (db/db mice)","journal":"Stem cell reviews and reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proximity ligation assay for direct binding, multiple knockdown experiments, in vivo model, single lab","pmids":["36627432"],"is_preprint":false},{"year":2024,"finding":"RPGR (retinitis pigmentosa GTPase regulator) is a guanine nucleotide exchange factor (GEF) for RAB37 that activates it by accelerating GDP-to-GTP exchange. RPGR directly interacts with RAB37 via the RPGR-RCC1-like domain. Rpgr knockout in mice leads to photoreceptor degeneration due to autophagy impairment; this is rescued by AAV-mediated restoration of RPGR, which re-activates RAB37-mediated autophagy.","method":"GEF activity assay (GDP-to-GTP exchange kinetics), Co-IP/direct interaction assay, Rpgr knockout mouse, AAV-mediated gene rescue, autophagy flux measurement in retina","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro GEF activity assay, direct interaction, KO mouse with defined phenotype, AAV rescue experiment, multiple orthogonal methods","pmids":["38536817"],"is_preprint":false},{"year":2024,"finding":"Rab37 mediates intracellular trafficking and plasma membrane presentation of PD-1 in T cells in a GTP-dependent manner. PD-1 co-localizes with Rab37-specific vesicles, and glycosylation-deficient PD-1 mutant shows delayed cargo recruitment to Rab37 vesicles and stalled membrane presentation. Tumor-infiltrating T cells from Rab37 knockout mice show upregulated proliferation and activity.","method":"Confocal imaging, biochemical co-localization, glycosylation mutant PD-1 analysis, Rab37 knockout mouse tumor model, GTP/GDP mutant analysis","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical and imaging approaches, GTP-dependence validated with mutants, KO mouse functional data, single lab","pmids":["38321486"],"is_preprint":false},{"year":2024,"finding":"Conditional knockout of Rab37 in oocytes impairs autophagy in the ovary and interferes with follicular homeostasis and ovary development in mice. E2F1 and EGR2 transcription factors synergistically activate Rab37 transcription and promote autophagy.","method":"Conditional knockout mouse model, autophagy flux assays, ChIP/promoter analysis for E2F1 and EGR2, flunarizine rescue experiment","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse with defined phenotype, transcription factor binding, rescue experiment, single lab","pmids":["39113565"],"is_preprint":false},{"year":2024,"finding":"GDP-bound Rab37 (inactive form) interacts with the nuclear localization sequence of STAT1 to sequester it in the cytosol, preventing STAT1 nuclear translocation and transcriptional activation of type I IFN pathway genes, thereby promoting M2-like macrophage polarization. This represents a vesicle trafficking-independent function of Rab37.","method":"cDNA microarray (Rab37 KO vs WT BMDMs), Co-IP of GDP-Rab37 with STAT1, subcellular fractionation showing STAT1 cytosolic retention, in vitro/in vivo assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with GDP-specific mutant, fractionation showing STAT1 sequestration, KO mouse BMDMs, single lab","pmids":["39984679"],"is_preprint":false},{"year":2024,"finding":"RAB37 promotes autophagic degradation of β-catenin in gastric cancer cells by strengthening the interaction between p62 and β-catenin; this requires RAB37 GTPase activity. The effect on EMT suppression, migration, and invasion is reversed by the autophagy inhibitor chloroquine.","method":"Co-IP (p62-β-catenin interaction), GTPase-dead mutant, autophagy inhibitor (chloroquine) rescue, Western blot for autophagy markers, in vivo pulmonary metastasis mouse model","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, pharmacological rescue, in vivo model, single lab","pmids":["39699800"],"is_preprint":false},{"year":2025,"finding":"Rab37 promotes osteopontin (OPN) secretion in macrophages, which activates STAT3 signaling to establish an autocrine feedback loop sustaining Spp1 expression and inducing M2-like polarization. Paracrine OPN signaling enhances lung cancer cell proliferation, migration, and invasion. Rab37 KO tumors showed higher proportion of Thbs1+ TAMs versus immunosuppressive Spp1+ TAMs in WT tumors.","method":"Single-cell RNA sequencing, Rab37 KO mouse tumor model, OPN secretion assay, STAT3 pathway analysis, paracrine co-culture experiments","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq, KO mouse, secretion assay, signaling pathway analysis, single lab","pmids":["41535255"],"is_preprint":false}],"current_model":"RAB37 is a small Rab GTPase that functions as a master regulator of vesicle exocytosis and autophagosome biogenesis: in its GTP-bound active state it directly binds ATG5 to recruit the ATG5-ATG12-ATG16L1 complex to the isolation membrane and facilitate LC3B lipidation; mediates GTP-dependent exocytosis of multiple secretory cargos (TIMP1, TIMP2, TSP1, SFRP1, sST2, IL-6, CHI3L1, OPN, Hsp90α) via VAMP8/Sec22b-SNARE machinery and secretory autophagy; is activated by the GEF RPGR (via GDP-to-GTP exchange through the RCC1-like domain); is inactivated by PKCα-mediated phosphorylation at T172; and in its GDP-bound state sequesters STAT1 in the cytosol to promote M2 macrophage polarization independently of vesicle trafficking."},"narrative":{"mechanistic_narrative":"RAB37 is a small Rab GTPase that operates as a master regulator of regulated exocytosis and autophagosome biogenesis, cycling between GTP- and GDP-bound states to control vesicle trafficking across secretory, immune, and metabolic cell types [PMID:25183545, PMID:29229996, PMID:38536817]. First identified on secretory granules of mast cells [PMID:10722846], RAB37 was subsequently shown to localize to insulin-containing dense-core granules in β-cells, where it controls granule docking and glucose-induced secretion through a mechanism distinct from Rab3a/Rab27a effectors [PMID:23826383], and to act as a negative regulator of mast-cell degranulation within a Rab27–Munc13-4–Rab37 complex [PMID:26931073]. In its GTP-bound active state, RAB37 drives nucleotide-dependent exocytosis of a broad panel of secretory cargos — including the metastasis suppressors TIMP1 and TIMP2, thrombospondin-1, and the Wnt antagonist SFRP1 — whose extracellular actions inactivate MMPs and suppress migration, angiogenesis, and cancer stemness [PMID:25183545, PMID:28151721, PMID:30158579, PMID:30131385]. This secretory output is executed through SNARE machinery, with VAMP8 and Sec22b required for trafficking and membrane fusion of RAB37–TIMP1 vesicles, the latter coupling cargo release to secretory autophagy [PMID:30165196, PMID:36457117, PMID:37151129]. Active RAB37 also directly binds ATG5 to recruit the ATG5–ATG12–ATG16L1 complex to the isolation membrane and facilitate LC3B lipidation, linking it mechanistically to autophagosome formation [PMID:29229996]; this autophagic activity additionally promotes p62-dependent autophagic degradation of β-catenin to suppress EMT [PMID:39699800]. RAB37 activity is gated by the GEF RPGR, which accelerates GDP-to-GTP exchange via its RCC1-like domain and is required for autophagy-dependent photoreceptor survival [PMID:38536817], and is switched off by PKCα phosphorylation at threonine 172, which attenuates the GTP-bound state and abrogates metastasis suppression [PMID:29312551]. In macrophages and T cells, RAB37 shapes the immune microenvironment by GTP-dependent secretion of IL-6, CHI3L1, sST2, and osteopontin and by trafficking PD-1 to the cell surface [PMID:29717487, PMID:34093869, PMID:34987649, PMID:38321486, PMID:41535255], while the GDP-bound form exerts a trafficking-independent role by sequestering STAT1 in the cytosol to drive M2 macrophage polarization [PMID:39984679].","teleology":[{"year":2000,"claim":"Establishing where a then-uncharacterized Rab acts: RAB37 was placed on secretory granules of mast cells, framing it as a candidate exocytic regulator.","evidence":"GFP-tagging and fluorescence microscopy in bone marrow mast cells","pmids":["10722846"],"confidence":"Medium","gaps":["No effector or cargo identified","Functional consequence for secretion not tested"]},{"year":2011,"claim":"First functional and interaction link: RAB37 controls TNF-α secretion from macrophages and engages the priming factor Munc13-1, connecting it to regulated exocytosis machinery.","evidence":"Overexpression/knockdown, LC-MS/MS interactome, co-localization in RAW264.7 macrophages","pmids":["21805469"],"confidence":"Medium","gaps":["Nucleotide dependence of the Munc13-1 interaction not resolved","Direct vs indirect binding not distinguished"]},{"year":2013,"claim":"Extending RAB37 to endocrine secretion and showing mechanistic independence: it docks insulin granules and supports glucose-induced secretion without using Rab3a/Rab27a effectors.","evidence":"Confocal localization, RNAi with secretion assay, pull-down in β-cell lines and human islets","pmids":["23826383"],"confidence":"Medium","gaps":["The distinct effector RAB37 uses in β-cells was not identified","GEF/GAP regulation in β-cells unknown"]},{"year":2014,"claim":"Defining a direct cargo and disease relevance: GTP-dependent RAB37 exocytosis of TIMP1 inactivates MMP9 to suppress metastasis, establishing a tumor-suppressive secretory axis.","evidence":"Secretomics, migration/invasion assays, tail-vein metastasis models, nucleotide-binding mutants","pmids":["25183545"],"confidence":"High","gaps":["SNARE machinery for TIMP1 release not yet defined","Upstream activator of RAB37 unknown at this stage"]},{"year":2016,"claim":"Revealing nucleotide-independent and inhibitory roles: RAB37 negatively regulates mast-cell degranulation within a Rab27–Munc13-4–Rab37 complex, and additionally suppresses metastasis by exocytosing thrombospondin-1.","evidence":"siRNA, dominant-active mutants, genetic epistasis, Co-IP in RBL-2H3 cells; migration/angiogenesis/in vivo metastasis assays in ESCC","pmids":["26931073","28151721"],"confidence":"High","gaps":["Structural basis of the Rab27–Munc13-4–Rab37 complex unresolved","How GTP-independent and GTP-dependent modes are partitioned in different cell types unclear"]},{"year":2017,"claim":"Connecting RAB37 to autophagosome biogenesis and identifying its off-switch: GTP-RAB37 directly binds ATG5 to nucleate ATG5-12-ATG16L1 assembly and LC3B lipidation, while PKCα phosphorylation at T172 inactivates it.","evidence":"Direct binding and Co-IP, GTP/GDP mutants, isolation-membrane localization, autophagy flux; in vitro PKCα kinase assay, T172D phospho-mimetic, in vivo metastasis","pmids":["29229996","29312551"],"confidence":"High","gaps":["Whether autophagic and secretory functions of RAB37 are mechanistically coupled not yet addressed","GEF activating RAB37 still unknown"]},{"year":2018,"claim":"Broadening the cargo repertoire and defining the fusion machinery: RAB37 secretes SFRP1, TIMP2, and sST2 via GTP-dependent exocytosis, and VAMP8 was identified as the v-SNARE required for RAB37-TIMP1 vesicle trafficking.","evidence":"Reconstitution and xenograft assays; co-localization, Co-IP, TIRF; in vivo lung-to-lung metastasis models in cancer cells","pmids":["30158579","30131385","29717487","30165196"],"confidence":"Medium","gaps":["Whether a single SNARE set handles all cargos or cargo-specific SNAREs exist not resolved","Selectivity determinants for distinct cargos unknown"]},{"year":2021,"claim":"Defining RAB37's immune-modulatory output: GTP-dependent IL-6 secretion drives M2 polarization and STAT3-dependent PD-1 expression in CD8+ T cells, while in stem cells RAB37 directly binds TIMP1 to drive CD63/integrin-β1/FAK adipogenic signaling.","evidence":"Vesicle isolation, imaging, ChIP, Rab37 KO syngeneic allografts; proximity ligation assay and knockdowns in hADSCs","pmids":["34093869","34858503"],"confidence":"High","gaps":["How RAB37 cargo selection skews toward immunosuppressive secretion not resolved","Direct vs vesicular contributions to immune phenotypes not fully separated"]},{"year":2022,"claim":"Formalizing secretory autophagy as the trafficking route: RAB37 and Sec22b are present in autophagosomes and required, with ATG5/ATG7, for TIMP1 exocytosis; RAB37 also traffics CHI3L1 to activate AKT/β-catenin/NF-κB.","evidence":"Autophagosome purification with mass spec, ATG5/ATG7/Sec22b knockdown, in vivo metastasis; vesicle isolation, TIRF, Rab37 KO splenocytes/BMDMs","pmids":["36457117","34987649"],"confidence":"High","gaps":["Trigger that diverts cargo into secretory vs degradative autophagy not defined","Stoichiometry of RAB37-Sec22b on the autophagosome unknown"]},{"year":2023,"claim":"Linking stimulus to dual output: starvation-activated GTP-RAB37 simultaneously increases LC3-II and drives Sec22b-dependent TIMP1 secretion, unifying autophagy activation and secretion; RAB37 also directly binds Hsp90α and TIMP1 to support angiogenic ADSC functions.","evidence":"Overexpression/knockdown, LC3-II immunoblotting, Sec22b siRNA, lung-to-lung metastasis; proximity ligation assay and LC-MS/MS of conditioned media in ADSCs, db/db wound model","pmids":["37151129","36627432"],"confidence":"Medium","gaps":["Mechanism coupling starvation sensing to RAB37 activation not defined","Whether Hsp90α and TIMP1 share the same vesicle population unresolved"]},{"year":2024,"claim":"Completing the regulatory cycle and revealing a trafficking-independent function: RPGR was identified as the GEF activating RAB37 to support retinal autophagy, while GDP-bound RAB37 sequesters STAT1 in the cytosol to promote M2 polarization; RAB37 also traffics PD-1, degrades β-catenin via p62, and is transcriptionally driven by E2F1/EGR2 for autophagy in oocytes.","evidence":"In vitro GEF kinetics, Co-IP, Rpgr KO mouse with AAV rescue; GDP-mutant Co-IP and fractionation in BMDMs; PD-1 glycosylation-mutant imaging and Rab37 KO tumors; p62-β-catenin Co-IP with chloroquine rescue; conditional oocyte KO with ChIP","pmids":["38536817","39984679","38321486","39699800","39113565"],"confidence":"High","gaps":["GAP that terminates RAB37 GTP signaling not identified","How the same protein partitions between exocytic, autophagic, and STAT1-sequestering roles in a given cell not resolved"]},{"year":2025,"claim":"Integrating RAB37 into a tumor-microenvironment feedback circuit: macrophage RAB37 promotes osteopontin secretion that sustains an autocrine STAT3/Spp1 loop enforcing M2 polarization and a Spp1+ immunosuppressive TAM state.","evidence":"Single-cell RNA sequencing, Rab37 KO tumor model, OPN secretion assay, paracrine co-culture","pmids":["41535255"],"confidence":"Medium","gaps":["Nucleotide-state requirement for OPN secretion vs STAT1 sequestration not disentangled","Therapeutic tractability of the OPN loop untested"]},{"year":null,"claim":"How a single Rab GTPase selects among its many cargos and partitions between GTP-dependent exocytosis, autophagosome biogenesis, and GDP-state STAT1 sequestration within one cell remains unresolved, as does the identity of its GAP.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No GAP identified for RAB37","No structural model of cargo-selective recognition","Spatial/temporal control distinguishing degradative vs secretory autophagy unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[4,7,11,16,20,24]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[23]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,17]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,3,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4,6,10,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,17,20,24]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,16,21,23,25]}],"complexes":["Rab27-Munc13-4-Rab37 complex","ATG5-ATG12-ATG16L1 complex"],"partners":["ATG5","VAMP8","SEC22B","RPGR","MUNC13-4","STAT1","HSP90AA1","SQSTM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96AX2","full_name":"Ras-related protein Rab-37","aliases":[],"length_aa":223,"mass_kda":24.8,"function":"The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:38536817). Acts as an organizer for autophagosome biogenesis in a GTP-dependent manner (PubMed:38536817). Involved in retinal homeostasis by autophagy regulation (PubMed:38536817)","subcellular_location":"Cytoplasmic vesicle; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q96AX2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB37","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RAB37","total_profiled":1310},"omim":[{"mim_id":"617812","title":"SOLUTE CARRIER FAMILY 35, MEMBER G2; SLC35G2","url":"https://www.omim.org/entry/617812"},{"mim_id":"609956","title":"RAS-ASSOCIATED PROTEIN RAB37; RAB37","url":"https://www.omim.org/entry/609956"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":23.1},{"tissue":"brain","ntpm":36.8},{"tissue":"lymphoid tissue","ntpm":19.8}],"url":"https://www.proteinatlas.org/search/RAB37"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96AX2","domains":[{"cath_id":"3.40.50.300","chopping":"27-219","consensus_level":"high","plddt":87.9453,"start":27,"end":219}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AX2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AX2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AX2-F1-predicted_aligned_error_v6.png","plddt_mean":83.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB37","jax_strain_url":"https://www.jax.org/strain/search?query=RAB37"},"sequence":{"accession":"Q96AX2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96AX2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96AX2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AX2"}},"corpus_meta":[{"pmid":"29229996","id":"PMC_29229996","title":"RAB37 interacts directly with ATG5 and promotes 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Rab37.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29312551","citation_count":13,"is_preprint":false},{"pmid":"38321486","id":"PMC_38321486","title":"Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.","date":"2024","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/38321486","citation_count":10,"is_preprint":false},{"pmid":"39113565","id":"PMC_39113565","title":"RAB37-mediated autophagy guards ovarian homeostasis and function.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39113565","citation_count":9,"is_preprint":false},{"pmid":"37151129","id":"PMC_37151129","title":"Secretory autophagy-promoted cargo exocytosis requires active RAB37.","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37151129","citation_count":9,"is_preprint":false},{"pmid":"38536817","id":"PMC_38536817","title":"RPGR is a guanine nucleotide exchange 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Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/39699800","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17971,"output_tokens":6746,"usd":0.077551,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15717,"output_tokens":4977,"usd":0.101505,"stage2_stop_reason":"end_turn"},"total_usd":0.179056,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Rab37 is a novel Rab GTPase specifically expressed in mast cells (MC-9 line and bone marrow mast cells) and localizes to secretory granules, as shown by GFP-tagged Rab37 expression in bone marrow mast cells.\",\n      \"method\": \"GFP-tagging and fluorescence microscopy in bone marrow mast cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with functional implication, single lab but clear subcellular localization result\",\n      \"pmids\": [\"10722846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rab37 controls TNF-α secretion from activated macrophages; overexpression of wild-type or constitutively active Rab37 increases TNF-α secretion while siRNA knockdown decreases it. Rab37 interacts with Munc13-1, and TNF-α-containing vesicles co-localize with both Rab37 and Munc13-1.\",\n      \"method\": \"Overexpression/knockdown (siRNA), LC-MS/MS interactome, immunocytochemistry co-localization in RAW264.7 macrophages\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (overexpression, knockdown, MS, co-localization), single lab\",\n      \"pmids\": [\"21805469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rab37 is identified as a MetAP-2-specific substrate; aberrant accumulation of Rab37 (when N-terminal methionine excision is blocked by MetAP-2 inhibitor TNP-470) disrupts Wnt planar cell polarity (PCP) signaling. A Rab37 point mutant resistant to NME phenocopies MetAP-2 inhibition on Wnt PCP-dependent processes.\",\n      \"method\": \"MetAP-2 inhibitor treatment, NME-resistant Rab37 point mutant expression, functional PCP signaling assays\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus functional rescue/phenocopy, single lab, two orthogonal approaches\",\n      \"pmids\": [\"22035799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rab37 localizes to insulin-containing large dense core granules in pancreatic β-cells, and its knockdown by RNAi impairs glucose-induced insulin secretion and reduces granule docking at the plasma membrane. Pull-down experiments show Rab37 does not interact with known Rab3a or Rab27a effectors, indicating it operates through a distinct mechanism.\",\n      \"method\": \"Confocal microscopy localization, RNAi knockdown with secretion assay, pull-down experiments in β-cell lines and human islets\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (localization, KD, pulldown), single lab\",\n      \"pmids\": [\"23826383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RAB37 directly targets TIMP1 as a secretory cargo and regulates TIMP1 exocytosis in a nucleotide-dependent (GTP-dependent) manner; secreted TIMP1 inactivates MMP9 to suppress cancer cell migration in vitro and in vivo. Dysfunction of RAB37 abrogates metastasis suppression.\",\n      \"method\": \"Secretomics, cell migration/invasion assays, animal (tail-vein injection) metastasis models, nucleotide-binding mutant analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (secretomics, in vitro assays, in vivo mouse models, mutant analysis), replicated across subsequent studies\",\n      \"pmids\": [\"25183545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In mast cells, Rab37 acts as a negative regulator of degranulation by interacting with Munc13-4 in a GTP-independent manner, forming a Rab27-Munc13-4-Rab37 complex that counteracts the vesicle-priming activity of the Rab27-Munc13-4 system. Knockdown of Rab37 or overexpression of dominant-active Rab37 both enhance degranulation; the hypersecretion phenotype in Rab37-knockdown cells is suppressed by simultaneous knockdown of Rab27a/b or Munc13-4.\",\n      \"method\": \"siRNA knockdown, dominant-active mutant overexpression, genetic epistasis (double knockdown), immunoprecipitation in RBL-2H3 mast cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis, Co-IP, multiple loss-of-function experiments with defined phenotypic readout, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26931073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab37-mediated exocytosis of thrombospondin-1 (TSP1) from cancer cells inhibits angiogenesis and suppresses metastasis; secreted TSP1 inhibits p-FAK/p-paxillin/p-ERK migration signaling in both cancer epithelial cells and surrounding endothelial cells. Dysfunction of Rab37 or loss of TSP1 abolishes these suppressive effects.\",\n      \"method\": \"Cell migration/invasion, angiogenesis, and in vivo metastasis assays; conditioned medium experiments; signaling pathway analysis in ESCC cells\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (in vitro and in vivo), single lab\",\n      \"pmids\": [\"28151721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RAB37 directly binds ATG5 and promotes autophagosome formation by recruiting ATG5-12 to the isolation membrane and facilitating assembly of the ATG5-ATG12-ATG16L1 complex. GTP-bound RAB37 shows enhanced interaction with ATG5-12, while GDP-stabilized mutation impairs the interaction. RAB37 promotes ATG5-12 interaction with ATG16L1, facilitating LC3B lipidation in a GTP-dependent manner.\",\n      \"method\": \"Direct binding assay, mutation analysis (GTP/GDP-binding mutants), Co-IP, isolation membrane localization, autophagy flux assays, knockdown and overexpression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding demonstrated, mutagenesis, multiple orthogonal methods (Co-IP, localization, functional assays), replicated in subsequent autophagy papers\",\n      \"pmids\": [\"29229996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PKCα phosphorylates Rab37 at threonine 172 (T172), leading to attenuation of its GTP-bound state, impairment of Rab37-mediated TIMP1 exocytosis, and reduction of metastasis suppression. Phospho-mimetic T172D mutant of Rab37 promotes tumor metastasis in vivo. PKCα reduces vesicle co-localization of Rab37 and TIMP1.\",\n      \"method\": \"In vitro kinase assay (PKCα phosphorylation of Rab37), site-directed mutagenesis (T172D phospho-mimetic), vesicle co-localization by confocal microscopy, in vivo metastasis assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, mutagenesis, in vivo validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29312551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab37 mediates exocytosis of secreted frizzled-related protein-1 (SFRP1), an extracellular Wnt antagonist, to suppress Wnt signaling and cancer stemness in vitro and in vivo. Reconstitution experiments show SFRP1 secretion is crucial for Rab37-mediated cancer stemness suppression.\",\n      \"method\": \"Reconstitution experiments, SFRP1 recombinant protein treatment, xenograft tumor initiation assay, signaling pathway analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution and in vivo experiments, single lab\",\n      \"pmids\": [\"30158579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VAMP8 (a v-SNARE) interacts with RAB37 and is required for TIMP1 exocytosis. VAMP8 co-localizes with RAB37 and facilitates trafficking of RAB37-TIMP1 vesicles. Reconstitution experiments (tail-vein injection, lung-to-lung metastasis) demonstrate VAMP8 is essential for RAB37-regulated vesicle trafficking of TIMP1 to suppress cancer metastasis.\",\n      \"method\": \"Confocal and TIRF microscopy, Co-IP, in vivo reconstitution assays (tail-vein injection, lung-to-lung metastasis mouse model)\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, live-cell imaging, in vivo reconstitution, single lab\",\n      \"pmids\": [\"30165196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab37 mediates secretion of soluble ST2 (sST2) from lung cancer cells in a GTP-dependent manner, and secreted sST2 skews macrophage polarization toward anti-tumoral M1-like phenotype both in vitro and in xenografts.\",\n      \"method\": \"Overexpression/knockdown system, GTP/GDP mutant analysis, macrophage polarization assays, xenograft tumor model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTP-dependent mutant analysis, in vitro and in vivo functional assays, single lab\",\n      \"pmids\": [\"29717487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAB37 co-localizes with TIMP2 and regulates TIMP2 secretion in nasopharyngeal carcinoma cells, thereby inhibiting MMP2 activity and suppressing cell metastasis. RAB37 downregulation is attributed to hypermethylation of its promoter.\",\n      \"method\": \"Co-localization assay, secretion assay, MMP2 activity assay, ectopic overexpression and in vivo validation\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (co-localization, secretion, enzymatic activity), single lab\",\n      \"pmids\": [\"30131385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB37 phosphorylation by PKCα (via the miR-200b/PKCα axis) is promoted by methionine treatment in gastric cancer stem cells, inactivating RAB37 and suppressing RAB37-mediated autophagy. Methionine also enhances RAB37 methylation. Methionine lyase (Metase) treatment reduces RAB37 phosphorylation and methylation, restoring autophagy.\",\n      \"method\": \"Lentiviral expression of methionine lyase, miR-200b/PKCα pathway analysis, methylation and phosphorylation assays, autophagy measurement in GCSCs\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (phosphorylation, methylation, autophagy flux), in vivo tumor model, single lab\",\n      \"pmids\": [\"32926650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab37 in macrophages regulates IL-6 secretion in a GTPase-dependent manner, promoting M2 macrophage polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. These mechanisms were demonstrated using vesicle isolation, imaging, and chromatin immunoprecipitation showing STAT3 binding to the PD-1 promoter.\",\n      \"method\": \"Vesicle isolation, imaging analyses, ChIP assay for STAT3 binding at PD-1 promoter, Rab37 knockout mice syngeneic allograft, GTP/GDP mutant analysis\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (vesicle isolation, imaging, ChIP, KO mouse model), mechanistic pathway established\",\n      \"pmids\": [\"34093869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB37 promotes adipogenic differentiation of hADSCs via TIMP1 secretion; RAB37 directly interacts with TIMP1 (shown by proximity ligation assay), and secreted TIMP1 signals through CD63/integrin β1 to promote FAK phosphorylation (Tyr397). Knockdown of TIMP1, CD63, or FAK inhibition impedes RAB37-mediated adipogenesis.\",\n      \"method\": \"Proximity ligation assay (direct interaction), cytokine array, ELISA, knockdown experiments, FAK phosphorylation assays in hADSCs\",\n      \"journal\": \"Stem cells international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proximity ligation assay for interaction, multiple knockdown experiments, single lab\",\n      \"pmids\": [\"34858503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rab37 mediates CHI3L1 (chitinase 3-like-1) intracellular vesicle trafficking and exocytosis in T cells and macrophages in a GTP-dependent manner; this is abolished in Rab37 knockout mice splenocytes and BMDMs, and attenuated with inactive GDP-bound Rab37. Secreted CHI3L1 activates AKT, β-catenin, and NF-κB signaling in cancer cells and macrophages.\",\n      \"method\": \"Vesicle isolation, TIRF microscopy, real-time confocal microscopy, Rab37 knockout mouse splenocytes/BMDMs, GTP/GDP mutant analysis\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (vesicle isolation, TIRF, confocal, KO mouse), GTP-dependence validated with mutants\",\n      \"pmids\": [\"34987649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Secretory autophagy promotes RAB37-mediated TIMP1 exocytosis in a RAB37- and Sec22b-dependent manner. Knockdown of Atg5 or Atg7 in cells harboring active RAB37 decreases autophagy and TIMP1 secretion. RAB37 and Sec22b proteins were identified in purified autophagosomes. Sec22b (a SNARE) participates in vesicle/membrane fusion of secretory autophagy.\",\n      \"method\": \"Autophagosome purification (mass spec identification of RAB37 and Sec22b), immunoblotting, TEM, immunofluorescence, siRNA knockdown of ATG5/ATG7/Sec22b, lung-to-lung metastasis mouse model\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — autophagosome purification with biochemical identification, multiple gene knockdowns, in vivo validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36457117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Starvation-activated RAB37 simultaneously drives autophagy activation and TIMP1 secretion via secretory autophagy in a Sec22b-dependent manner. Active GTP-bound RAB37 increases LC3-II levels and TIMP1 secretion; knockdown of Sec22b decreases TIMP1 secretion without affecting proliferation.\",\n      \"method\": \"Overexpression/knockdown system, LC3-II immunoblotting, motility assays, lung-to-lung mouse metastasis model, Sec22b siRNA\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo assays, mechanistic confirmation with Sec22b knockdown, single lab\",\n      \"pmids\": [\"37151129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rab37 directly binds Hsp90α and TIMP1 in ADSCs (shown by proximity ligation assay), regulates their secretion, and promotes ADSC proliferation, migration, and endothelial differentiation. Knockdown of Hsp90α or TIMP1 compromises Rab37's promoting effects.\",\n      \"method\": \"Proximity ligation assay, LC-MS/MS of conditioned media, ELISA, knockdown experiments, in vivo diabetic wound healing model (db/db mice)\",\n      \"journal\": \"Stem cell reviews and reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proximity ligation assay for direct binding, multiple knockdown experiments, in vivo model, single lab\",\n      \"pmids\": [\"36627432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RPGR (retinitis pigmentosa GTPase regulator) is a guanine nucleotide exchange factor (GEF) for RAB37 that activates it by accelerating GDP-to-GTP exchange. RPGR directly interacts with RAB37 via the RPGR-RCC1-like domain. Rpgr knockout in mice leads to photoreceptor degeneration due to autophagy impairment; this is rescued by AAV-mediated restoration of RPGR, which re-activates RAB37-mediated autophagy.\",\n      \"method\": \"GEF activity assay (GDP-to-GTP exchange kinetics), Co-IP/direct interaction assay, Rpgr knockout mouse, AAV-mediated gene rescue, autophagy flux measurement in retina\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro GEF activity assay, direct interaction, KO mouse with defined phenotype, AAV rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"38536817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rab37 mediates intracellular trafficking and plasma membrane presentation of PD-1 in T cells in a GTP-dependent manner. PD-1 co-localizes with Rab37-specific vesicles, and glycosylation-deficient PD-1 mutant shows delayed cargo recruitment to Rab37 vesicles and stalled membrane presentation. Tumor-infiltrating T cells from Rab37 knockout mice show upregulated proliferation and activity.\",\n      \"method\": \"Confocal imaging, biochemical co-localization, glycosylation mutant PD-1 analysis, Rab37 knockout mouse tumor model, GTP/GDP mutant analysis\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical and imaging approaches, GTP-dependence validated with mutants, KO mouse functional data, single lab\",\n      \"pmids\": [\"38321486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional knockout of Rab37 in oocytes impairs autophagy in the ovary and interferes with follicular homeostasis and ovary development in mice. E2F1 and EGR2 transcription factors synergistically activate Rab37 transcription and promote autophagy.\",\n      \"method\": \"Conditional knockout mouse model, autophagy flux assays, ChIP/promoter analysis for E2F1 and EGR2, flunarizine rescue experiment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse with defined phenotype, transcription factor binding, rescue experiment, single lab\",\n      \"pmids\": [\"39113565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GDP-bound Rab37 (inactive form) interacts with the nuclear localization sequence of STAT1 to sequester it in the cytosol, preventing STAT1 nuclear translocation and transcriptional activation of type I IFN pathway genes, thereby promoting M2-like macrophage polarization. This represents a vesicle trafficking-independent function of Rab37.\",\n      \"method\": \"cDNA microarray (Rab37 KO vs WT BMDMs), Co-IP of GDP-Rab37 with STAT1, subcellular fractionation showing STAT1 cytosolic retention, in vitro/in vivo assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with GDP-specific mutant, fractionation showing STAT1 sequestration, KO mouse BMDMs, single lab\",\n      \"pmids\": [\"39984679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAB37 promotes autophagic degradation of β-catenin in gastric cancer cells by strengthening the interaction between p62 and β-catenin; this requires RAB37 GTPase activity. The effect on EMT suppression, migration, and invasion is reversed by the autophagy inhibitor chloroquine.\",\n      \"method\": \"Co-IP (p62-β-catenin interaction), GTPase-dead mutant, autophagy inhibitor (chloroquine) rescue, Western blot for autophagy markers, in vivo pulmonary metastasis mouse model\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, pharmacological rescue, in vivo model, single lab\",\n      \"pmids\": [\"39699800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rab37 promotes osteopontin (OPN) secretion in macrophages, which activates STAT3 signaling to establish an autocrine feedback loop sustaining Spp1 expression and inducing M2-like polarization. Paracrine OPN signaling enhances lung cancer cell proliferation, migration, and invasion. Rab37 KO tumors showed higher proportion of Thbs1+ TAMs versus immunosuppressive Spp1+ TAMs in WT tumors.\",\n      \"method\": \"Single-cell RNA sequencing, Rab37 KO mouse tumor model, OPN secretion assay, STAT3 pathway analysis, paracrine co-culture experiments\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq, KO mouse, secretion assay, signaling pathway analysis, single lab\",\n      \"pmids\": [\"41535255\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB37 is a small Rab GTPase that functions as a master regulator of vesicle exocytosis and autophagosome biogenesis: in its GTP-bound active state it directly binds ATG5 to recruit the ATG5-ATG12-ATG16L1 complex to the isolation membrane and facilitate LC3B lipidation; mediates GTP-dependent exocytosis of multiple secretory cargos (TIMP1, TIMP2, TSP1, SFRP1, sST2, IL-6, CHI3L1, OPN, Hsp90α) via VAMP8/Sec22b-SNARE machinery and secretory autophagy; is activated by the GEF RPGR (via GDP-to-GTP exchange through the RCC1-like domain); is inactivated by PKCα-mediated phosphorylation at T172; and in its GDP-bound state sequesters STAT1 in the cytosol to promote M2 macrophage polarization independently of vesicle trafficking.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB37 is a small Rab GTPase that operates as a master regulator of regulated exocytosis and autophagosome biogenesis, cycling between GTP- and GDP-bound states to control vesicle trafficking across secretory, immune, and metabolic cell types [#4, #7, #20]. First identified on secretory granules of mast cells [#0], RAB37 was subsequently shown to localize to insulin-containing dense-core granules in β-cells, where it controls granule docking and glucose-induced secretion through a mechanism distinct from Rab3a/Rab27a effectors [#3], and to act as a negative regulator of mast-cell degranulation within a Rab27–Munc13-4–Rab37 complex [#5]. In its GTP-bound active state, RAB37 drives nucleotide-dependent exocytosis of a broad panel of secretory cargos — including the metastasis suppressors TIMP1 and TIMP2, thrombospondin-1, and the Wnt antagonist SFRP1 — whose extracellular actions inactivate MMPs and suppress migration, angiogenesis, and cancer stemness [#4, #6, #9, #12]. This secretory output is executed through SNARE machinery, with VAMP8 and Sec22b required for trafficking and membrane fusion of RAB37–TIMP1 vesicles, the latter coupling cargo release to secretory autophagy [#10, #17, #18]. Active RAB37 also directly binds ATG5 to recruit the ATG5–ATG12–ATG16L1 complex to the isolation membrane and facilitate LC3B lipidation, linking it mechanistically to autophagosome formation [#7]; this autophagic activity additionally promotes p62-dependent autophagic degradation of β-catenin to suppress EMT [#24]. RAB37 activity is gated by the GEF RPGR, which accelerates GDP-to-GTP exchange via its RCC1-like domain and is required for autophagy-dependent photoreceptor survival [#20], and is switched off by PKCα phosphorylation at threonine 172, which attenuates the GTP-bound state and abrogates metastasis suppression [#8]. In macrophages and T cells, RAB37 shapes the immune microenvironment by GTP-dependent secretion of IL-6, CHI3L1, sST2, and osteopontin and by trafficking PD-1 to the cell surface [#11, #14, #16, #21, #25], while the GDP-bound form exerts a trafficking-independent role by sequestering STAT1 in the cytosol to drive M2 macrophage polarization [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing where a then-uncharacterized Rab acts: RAB37 was placed on secretory granules of mast cells, framing it as a candidate exocytic regulator.\",\n      \"evidence\": \"GFP-tagging and fluorescence microscopy in bone marrow mast cells\",\n      \"pmids\": [\"10722846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No effector or cargo identified\", \"Functional consequence for secretion not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"First functional and interaction link: RAB37 controls TNF-α secretion from macrophages and engages the priming factor Munc13-1, connecting it to regulated exocytosis machinery.\",\n      \"evidence\": \"Overexpression/knockdown, LC-MS/MS interactome, co-localization in RAW264.7 macrophages\",\n      \"pmids\": [\"21805469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nucleotide dependence of the Munc13-1 interaction not resolved\", \"Direct vs indirect binding not distinguished\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extending RAB37 to endocrine secretion and showing mechanistic independence: it docks insulin granules and supports glucose-induced secretion without using Rab3a/Rab27a effectors.\",\n      \"evidence\": \"Confocal localization, RNAi with secretion assay, pull-down in β-cell lines and human islets\",\n      \"pmids\": [\"23826383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The distinct effector RAB37 uses in β-cells was not identified\", \"GEF/GAP regulation in β-cells unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining a direct cargo and disease relevance: GTP-dependent RAB37 exocytosis of TIMP1 inactivates MMP9 to suppress metastasis, establishing a tumor-suppressive secretory axis.\",\n      \"evidence\": \"Secretomics, migration/invasion assays, tail-vein metastasis models, nucleotide-binding mutants\",\n      \"pmids\": [\"25183545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SNARE machinery for TIMP1 release not yet defined\", \"Upstream activator of RAB37 unknown at this stage\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealing nucleotide-independent and inhibitory roles: RAB37 negatively regulates mast-cell degranulation within a Rab27–Munc13-4–Rab37 complex, and additionally suppresses metastasis by exocytosing thrombospondin-1.\",\n      \"evidence\": \"siRNA, dominant-active mutants, genetic epistasis, Co-IP in RBL-2H3 cells; migration/angiogenesis/in vivo metastasis assays in ESCC\",\n      \"pmids\": [\"26931073\", \"28151721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Rab27–Munc13-4–Rab37 complex unresolved\", \"How GTP-independent and GTP-dependent modes are partitioned in different cell types unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connecting RAB37 to autophagosome biogenesis and identifying its off-switch: GTP-RAB37 directly binds ATG5 to nucleate ATG5-12-ATG16L1 assembly and LC3B lipidation, while PKCα phosphorylation at T172 inactivates it.\",\n      \"evidence\": \"Direct binding and Co-IP, GTP/GDP mutants, isolation-membrane localization, autophagy flux; in vitro PKCα kinase assay, T172D phospho-mimetic, in vivo metastasis\",\n      \"pmids\": [\"29229996\", \"29312551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autophagic and secretory functions of RAB37 are mechanistically coupled not yet addressed\", \"GEF activating RAB37 still unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Broadening the cargo repertoire and defining the fusion machinery: RAB37 secretes SFRP1, TIMP2, and sST2 via GTP-dependent exocytosis, and VAMP8 was identified as the v-SNARE required for RAB37-TIMP1 vesicle trafficking.\",\n      \"evidence\": \"Reconstitution and xenograft assays; co-localization, Co-IP, TIRF; in vivo lung-to-lung metastasis models in cancer cells\",\n      \"pmids\": [\"30158579\", \"30131385\", \"29717487\", \"30165196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether a single SNARE set handles all cargos or cargo-specific SNAREs exist not resolved\", \"Selectivity determinants for distinct cargos unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining RAB37's immune-modulatory output: GTP-dependent IL-6 secretion drives M2 polarization and STAT3-dependent PD-1 expression in CD8+ T cells, while in stem cells RAB37 directly binds TIMP1 to drive CD63/integrin-β1/FAK adipogenic signaling.\",\n      \"evidence\": \"Vesicle isolation, imaging, ChIP, Rab37 KO syngeneic allografts; proximity ligation assay and knockdowns in hADSCs\",\n      \"pmids\": [\"34093869\", \"34858503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB37 cargo selection skews toward immunosuppressive secretion not resolved\", \"Direct vs vesicular contributions to immune phenotypes not fully separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Formalizing secretory autophagy as the trafficking route: RAB37 and Sec22b are present in autophagosomes and required, with ATG5/ATG7, for TIMP1 exocytosis; RAB37 also traffics CHI3L1 to activate AKT/β-catenin/NF-κB.\",\n      \"evidence\": \"Autophagosome purification with mass spec, ATG5/ATG7/Sec22b knockdown, in vivo metastasis; vesicle isolation, TIRF, Rab37 KO splenocytes/BMDMs\",\n      \"pmids\": [\"36457117\", \"34987649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that diverts cargo into secretory vs degradative autophagy not defined\", \"Stoichiometry of RAB37-Sec22b on the autophagosome unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linking stimulus to dual output: starvation-activated GTP-RAB37 simultaneously increases LC3-II and drives Sec22b-dependent TIMP1 secretion, unifying autophagy activation and secretion; RAB37 also directly binds Hsp90α and TIMP1 to support angiogenic ADSC functions.\",\n      \"evidence\": \"Overexpression/knockdown, LC3-II immunoblotting, Sec22b siRNA, lung-to-lung metastasis; proximity ligation assay and LC-MS/MS of conditioned media in ADSCs, db/db wound model\",\n      \"pmids\": [\"37151129\", \"36627432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling starvation sensing to RAB37 activation not defined\", \"Whether Hsp90α and TIMP1 share the same vesicle population unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Completing the regulatory cycle and revealing a trafficking-independent function: RPGR was identified as the GEF activating RAB37 to support retinal autophagy, while GDP-bound RAB37 sequesters STAT1 in the cytosol to promote M2 polarization; RAB37 also traffics PD-1, degrades β-catenin via p62, and is transcriptionally driven by E2F1/EGR2 for autophagy in oocytes.\",\n      \"evidence\": \"In vitro GEF kinetics, Co-IP, Rpgr KO mouse with AAV rescue; GDP-mutant Co-IP and fractionation in BMDMs; PD-1 glycosylation-mutant imaging and Rab37 KO tumors; p62-β-catenin Co-IP with chloroquine rescue; conditional oocyte KO with ChIP\",\n      \"pmids\": [\"38536817\", \"39984679\", \"38321486\", \"39699800\", \"39113565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GAP that terminates RAB37 GTP signaling not identified\", \"How the same protein partitions between exocytic, autophagic, and STAT1-sequestering roles in a given cell not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrating RAB37 into a tumor-microenvironment feedback circuit: macrophage RAB37 promotes osteopontin secretion that sustains an autocrine STAT3/Spp1 loop enforcing M2 polarization and a Spp1+ immunosuppressive TAM state.\",\n      \"evidence\": \"Single-cell RNA sequencing, Rab37 KO tumor model, OPN secretion assay, paracrine co-culture\",\n      \"pmids\": [\"41535255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nucleotide-state requirement for OPN secretion vs STAT1 sequestration not disentangled\", \"Therapeutic tractability of the OPN loop untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single Rab GTPase selects among its many cargos and partitions between GTP-dependent exocytosis, autophagosome biogenesis, and GDP-state STAT1 sequestration within one cell remains unresolved, as does the identity of its GAP.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No GAP identified for RAB37\", \"No structural model of cargo-selective recognition\", \"Spatial/temporal control distinguishing degradative vs secretory autophagy unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [4, 7, 11, 16, 20, 24]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 3, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005776\", \"supporting_discovery_ids\": [7, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4, 6, 10, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 17, 20, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 16, 21, 23, 25]}\n    ],\n    \"complexes\": [\n      \"Rab27-Munc13-4-Rab37 complex\",\n      \"ATG5-ATG12-ATG16L1 complex\"\n    ],\n    \"partners\": [\n      \"ATG5\",\n      \"VAMP8\",\n      \"Sec22b\",\n      \"RPGR\",\n      \"Munc13-4\",\n      \"STAT1\",\n      \"Hsp90AA1\",\n      \"SQSTM1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}