{"gene":"RAB26","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2015,"finding":"Rab26 (GTP-bound/active form) specifically associates with clusters of synaptic vesicles in neurites and directs synaptic and secretory vesicles into preautophagosomal structures co-localizing with Atg16L1, LC3B, and Rab33B. Atg16L1 was identified as a direct effector of Rab26, binding selectively to the GTP-bound form of Rab26.","method":"Overexpression of active vs. GDP-preferring Rab26 mutants in neurons, co-localization with autophagy markers, direct binding assay (Atg16L1 as effector)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional mutant analysis, direct effector binding demonstrated, replicated across multiple cell systems and later by independent labs","pmids":["25643395"],"is_preprint":false},{"year":2009,"finding":"RAB26 is a direct transcriptional target of the transcription factor MIST1, which binds conserved CATATG E-boxes in the RAB26 promoter to activate its transcription. RAB26 activity (alongside RAB3D) is required for the formation of large secretory granules in gastric zymogenic cells; dominant-negative RAB26 and RAB prenylation inhibitors abrogate granule formation.","method":"ChIP/EMSA showing MIST1 binding to RAB26 E-boxes; dominant-negative RAB26 transfection; RAB prenylation inhibitor treatment; RFP-pepsinogen C granule formation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter binding demonstrated, loss-of-function with dominant-negative and chemical inhibitor, specific granule formation phenotype, multiple orthogonal methods","pmids":["20038531"],"is_preprint":false},{"year":2000,"finding":"Rab26 protein localizes specifically to secretory granule membranes in parotid acinar cells, binds GTP, and its immunostaining disappears after isoproterenol treatment, consistent with a role in regulated secretory granule exocytosis.","method":"Western blotting with GTP-binding assay ([α-32P]GTP), subcellular fractionation, immunocytochemistry (light and electron microscopy)","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct GTP-binding demonstrated, subcellular fractionation and EM localization, single lab","pmids":["10857477"],"is_preprint":false},{"year":2005,"finding":"Rab26 localizes to mature (not immature) secretory granule membranes in parotid acinar cells. Anti-Rab26 antibody inhibits isoproterenol (β-adrenergic/cAMP)-induced amylase release from permeabilized acinar cells but has no effect on Ca2+-induced amylase release, indicating a selective role in cAMP-dependent granule recruitment to the plasma membrane.","method":"Percoll-sucrose density gradient fractionation; antibody inhibition of exocytosis in streptolysin-O-permeabilized acinar cells; amylase secretion assay","journal":"Archives of oral biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional antibody-inhibition assay in permeabilized cells with specific agonist selectivity, single lab","pmids":["16076461"],"is_preprint":false},{"year":2012,"finding":"Rab26 regulates anterograde transport of α2A- and α2B-adrenergic receptors from the Golgi to the cell surface. Rab26 mutants and siRNA-mediated knockdown arrest receptors in the Golgi and reduce cell surface receptor numbers. Rab26 directly and activation-dependently interacts with the third intracellular loop of α2B-AR.","method":"Rab26 mutant overexpression and siRNA knockdown; cell surface receptor quantification; co-immunoprecipitation/pulldown demonstrating direct GTP-dependent interaction with α2B-AR third intracellular loop","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct GTP-dependent binding shown, Golgi arrest phenotype with two independent loss-of-function approaches (mutant + siRNA), functional ERK1/2 readout","pmids":["23105096"],"is_preprint":false},{"year":2014,"finding":"RAB26 associates predominantly with LAMP1/cathepsin D-positive lysosomes (not secretory granules) and drives lysosome coalescence into a central perinuclear region. Lysosome clustering caused by increased RAB26 expression in turn redistributes mitochondria into distinct subcellular neighborhoods.","method":"Fluorescence co-localization with lysosomal and secretory granule markers; induction of zymogen-secreting cell differentiation; direct transfection of RAB26","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct subcellular localization with functional consequence (lysosome clustering, mitochondria redistribution), single lab, two induction approaches","pmids":["24413166"],"is_preprint":false},{"year":2018,"finding":"RAB26 promotes autophagic degradation of phosphorylated (active) SRC kinase in endothelial cells through direct, GTP-dependent interaction with ATG16L1. Loss of RAB26 leads to SRC phosphorylation, CDH5/VE-cadherin phosphorylation, CDH5 internalization, and disruption of adherens junctions, increasing vascular permeability in acute lung injury.","method":"RAB26 knockout mice (vascular permeability assays), siRNA depletion and overexpression in HPMECs, co-immunoprecipitation of RAB26 with ATG16L1 (GTP-dependent), western blot for phospho-SRC and phospho-CDH5","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo KO with defined permeability phenotype, overexpression rescue, consistent with prior ATG16L1 effector finding from independent lab","pmids":["29965781"],"is_preprint":false},{"year":2019,"finding":"RAB26 is a critical target of SNRPB-mediated splicing regulation in NSCLC; SNRPB depletion causes intron 7 retention in RAB26 mRNA, triggering nonsense-mediated decay (NMD) and reducing RAB26 protein levels. Forced RAB26 re-expression partially rescues decreased tumorigenicity caused by SNRPB depletion.","method":"siRNA knockdown of SNRPB; RT-PCR demonstrating intron retention; NMD pathway analysis; RAB26 re-expression rescue assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — splicing mechanism demonstrated by RT-PCR, rescue experiment confirms functional link, single lab","pmids":["31511502"],"is_preprint":false},{"year":2020,"finding":"The Coxiella burnetii effector protein CvpF specifically interacts with host RAB26, recruiting the autophagosomal marker LC3B to Coxiella-containing vacuoles, thereby subverting RAB26-dependent autophagy to promote vacuole biogenesis and bacterial virulence.","method":"Transposon mutant library screen; co-immunoprecipitation/pulldown of CvpF with RAB26; LC3B recruitment assay; SCID mouse virulence model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction shown, functional consequence in vacuole biogenesis and in vivo virulence, single lab","pmids":["32116095"],"is_preprint":false},{"year":2021,"finding":"Rab26 mediates autophagic degradation of phosphorylated Src kinase in breast cancer cells through interaction with ATG16L1. Rab26 promotes endosomal translocation of Src and reduces Src at focal adhesions, thereby suppressing cell migration and invasion.","method":"Rab26 overexpression and knockdown; immunofluorescence co-localization of Src with endosomal markers; Co-IP with ATG16L1; migration/invasion assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with ATG16L1, subcellular redistribution of Src shown, functional phenotype in migration/invasion, single lab","pmids":["33731709"],"is_preprint":false},{"year":2021,"finding":"Rab26 regulates cell surface transport of the erythropoietin receptor (EPOR) in macrophages; loss of Rab26 reduces surface EPOR levels, impairs EPO-mediated M2 macrophage polarization, and tips macrophage phenotype toward M1.","method":"Rab26 KO mice; macrophage polarization assays; cell surface EPOR measurement after Rab26 modulation","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined polarization phenotype, EPOR surface levels quantified, single lab","pmids":["34925338"],"is_preprint":false},{"year":2022,"finding":"SMAD3 transcriptionally activates RAB26 by binding to the RAB26 promoter, as demonstrated by dual-luciferase reporter and chromatin immunoprecipitation assays. SMAD3 overexpression blocks inhibitory effects of RAB26 silencing on NSCLC cell proliferation, migration, and invasion.","method":"Dual-luciferase reporter assay; chromatin immunoprecipitation (ChIP); RAB26 shRNA knockdown; SMAD3 overexpression rescue","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP and luciferase reporter, functional rescue, single lab","pmids":["35291909"],"is_preprint":false},{"year":2022,"finding":"In Drosophila salivary glands, Rab26 localizes to immature secretory glue granules and prevents their acidification and premature maturation. Rab26 loss accelerates granule maturation, acidification, fusion, and lysosomal breakdown (crinophagy). Loss of Mon1 (an activator of Rab7) causes Rab26 to remain on large granules, implicating a Mon1-Rab7 pathway that counteracts Rab26 to drive granule maturation.","method":"Rab26 mutant Drosophila; fluorescence microscopy of glue granule acidification and fusion; genetic epistasis with Mon1 mutant; overexpression studies","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined granule maturation phenotype, epistasis with Mon1, Drosophila ortholog","pmids":["36600084"],"is_preprint":false},{"year":2022,"finding":"Manganese-induced α-synuclein overexpression suppresses Rab26-ATG16L1 co-localization and reduces LC3II-positive synaptic vesicles, impairing Rab26-dependent autophagy initiation and causing accumulation of dysfunctional synaptic vesicles. Knockdown of α-synuclein with shRNA restores Rab26-ATG16L1 co-localization in Mn-exposed neurons.","method":"α-synuclein shRNA knockdown in primary hippocampal neurons; co-localization of Rab26 with ATG16L1 and LC3II-positive SVs by immunofluorescence; in vivo Mn exposure mouse model","journal":"The Science of the total environment","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic rescue with shRNA showing restored Rab26-ATG16L1 co-localization, in vivo and in vitro concordance, single lab","pmids":["36341850"],"is_preprint":false},{"year":2023,"finding":"Rab26 directly interacts with synaptotagmin-1 (Syt1) via the Syt1 C2A domain (shown by GST pulldown), interfering with Syt1-SNAP25 interaction and inhibiting exocytosis of newcomer insulin granules. Rab26 knockout mice show increased glucose-stimulated insulin secretion, and Rab26 overexpression in islets suppresses insulin secretion; Rab26 overexpression causes clustering of insulin granules.","method":"Rab26-/- mice (CRISPR/Cas9); GST pulldown of Rab26 with Syt1 C2A domain; TIRF microscopy of insulin granule exocytosis; Rab26 KD in insulinoma cells; islet transplantation assay","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct in vitro binding assay, KO mouse with physiological phenotype, TIRF single-granule imaging, multiple orthogonal methods in one study","pmids":["37289842"],"is_preprint":false},{"year":2023,"finding":"Rab26 interacts with mitochondrial fusion protein MFN2 and regulates MFN2 transport to mitochondria. Rab26 deficiency reduces mitochondrial MFN2 levels, decreases mitochondrial ROS and ATP production, and impairs macrophage phagocytosis and bacterial clearance.","method":"Co-immunoprecipitation of Rab26 with MFN2; Rab26 KO bone marrow-derived macrophages; MFN2 siRNA knockdown; mitochondrial ROS and ATP measurement; phagocytosis/bacterial killing assays; in vivo ARDS mouse model","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, KO with defined mitochondrial and phagocytosis phenotype, siRNA epistasis, single lab","pmids":["37060270"],"is_preprint":false},{"year":2023,"finding":"KLF4 transcriptionally targets RAB26 (verified by luciferase reporter assay) to inhibit autophagy in colon cancer cells. KLF4 overexpression suppresses LC3II/I ratio and autophagosome formation; RAB26 knockdown or rapamycin treatment reverses this effect and restores 5-FU resistance.","method":"Luciferase reporter assay for KLF4-RAB26 promoter interaction; RAB26 shRNA knockdown; autophagosome imaging by confocal microscopy; 5-FU resistance assay; xenograft mouse model","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct promoter interaction by luciferase assay, genetic rescue epistasis, single lab","pmids":["37431852"],"is_preprint":false},{"year":2023,"finding":"ROS/cigarette smoke exposure induces DNMT3b-mediated hypermethylation of the Rab26 promoter, suppressing Rab26 expression. Reduced Rab26 activates p38 and JNK MAPK signaling to promote airway epithelial inflammatory mediator production; Rab26 overexpression attenuates this response.","method":"Rab26 promoter methylation assay; DNMT3b siRNA; antioxidant (NAC) and DNA methylation inhibitor (5-AZA) treatment; Rab26 overexpression/silencing with p38/JNK phosphorylation readouts; in vivo smoking mouse model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — promoter methylation mechanism validated, MAPK pathway placement by OE/KD, multiple in vitro and in vivo approaches, single lab","pmids":["36610560"],"is_preprint":false},{"year":2025,"finding":"Rab26 interacts with angiotensin II Type 1 receptor (AT1R) and promotes its transport to the cell surface in pulmonary artery smooth muscle cells (PASMCs), thereby activating STAT3 and upregulating/promoting nuclear translocation of YAP1, driving PASMC hyper-proliferation under hypoxia.","method":"Co-immunoprecipitation of Rab26 with AT1R; Rab26 KO mice (PAH model); pharmacological inhibition of AT1R and pSTAT3; assessment of pSTAT3 and YAP1 levels; pulmonary vascular remodeling histology","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP interaction, KO mouse with vascular remodeling phenotype, pharmacological epistasis, single lab","pmids":["41231254"],"is_preprint":false},{"year":2025,"finding":"Rab26 deficiency in mice causes depression/anxiety-like behaviors and cognitive impairment. Mechanistically, Rab26 interacts with the serotonin transporter SERT and promotes its autophagic degradation; loss of Rab26 increases cell surface SERT levels, reduces synaptic vesicle turnover (accumulation of SVs at presynaptic terminals), and decreases mEPSC frequency and LTP.","method":"Rab26-/- mice; behavioral tests; co-immunoprecipitation of Rab26 with SERT; cell surface SERT measurement; electrophysiology (mEPSC, LTP); electron microscopy of SV accumulation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, KO mouse with multiple orthogonal phenotypes (behavioral, electrophysiological, ultrastructural), single lab","pmids":["40687824"],"is_preprint":false},{"year":2025,"finding":"Rab26 facilitates lysosomal translocation and degradation of eukaryotic elongation factor 1A (eEF1A) in cardiomyocytes. Cardiac-specific Rab26 overexpression (via AAV9) reduces eEF1A levels, improving cardiac function and reducing hypertrophy; eEF1A silencing eliminates the cardioprotective effect of Rab26.","method":"Protein interaction studies (Co-IP/pulldown); fluorescence co-localization of Rab26 and eEF1A with lysosomes; protease inhibition assays; AAV9-cardiac-specific Rab26 overexpression; Rab26 KO; TAC mouse model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction, lysosomal co-localization with protease inhibition confirmation, epistasis via eEF1A silencing, KO and OE mouse models, single lab","pmids":["40609824"],"is_preprint":false},{"year":2026,"finding":"Rab26 physically binds to mitochondrial VDAC1 and prevents its oligomerization. Loss of Rab26 promotes VDAC1 oligomerization, mitochondrial membrane permeabilization, and mtDNA leakage into the cytosol, which hyperactivates cGAS-STING signaling, represses SLC7A11/GPX4, and drives ferroptosis in airway epithelial cells exposed to cigarette smoke.","method":"Co-immunoprecipitation; chemical cross-linking; transmission electron microscopy; Rab26-/- mice; pharmacological STING inhibition; GPX4/SLC7A11 western blot","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Rab26-VDAC1 interaction by Co-IP and cross-linking, TEM ultrastructure, KO mouse with in vivo phenotype, pharmacological epistasis, single lab","pmids":["42176907"],"is_preprint":false},{"year":2026,"finding":"Rab26 stabilizes EPOR by preventing its ubiquitin-mediated proteasomal degradation; Rab26 deficiency upregulates the E3 ligase BTRC, which interacts with EPOR to promote EPOR degradation. This reduces EPOR levels, suppresses the PPARγ/GPX4 and PINK1-mediated mitophagy axes, and sensitizes macrophages to ferroptosis.","method":"Co-IP of BTRC with EPOR; Rab26 KO macrophages; EPOR and BTRC protein level measurement; PPARγ antagonism; mitophagy assays; ferroptosis (lipid peroxidation, GPX4) assays; CLP sepsis mouse model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP of BTRC-EPOR interaction, KO mouse with in vivo sepsis phenotype, pharmacological epistasis of PPARγ and PINK1 pathway, single lab","pmids":["42086108"],"is_preprint":false}],"current_model":"RAB26 is a GTP-binding small GTPase that, in its active (GTP-bound) state, directly engages ATG16L1 as an effector to link synaptic/secretory vesicles and lysosomes to preautophagosomal structures for selective autophagic degradation; it also coordinates anterograde Golgi-to-plasma-membrane trafficking of multiple receptors (α2-adrenergic receptors, EPOR, AT1R), sequesters synaptotagmin-1 to restrain insulin granule exocytosis, interacts with VDAC1 to protect mitochondrial integrity, and is transcriptionally regulated by MIST1 (in secretory cells), SMAD3, and KLF4, with its expression suppressed by ROS-driven promoter hypermethylation."},"narrative":{"mechanistic_narrative":"RAB26 is a GTP-binding small GTPase that coordinates membrane trafficking and selective autophagy of secretory and synaptic vesicles, lysosomes, and surface receptors [PMID:25643395, PMID:37289842]. In its active GTP-bound state it engages ATG16L1 as a direct effector, routing synaptic and secretory vesicles into preautophagosomal structures marked by LC3B and Rab33B for autophagic degradation [PMID:25643395]; this RAB26–ATG16L1 axis targets active phosphorylated SRC for degradation, thereby maintaining endothelial adherens junctions and limiting vascular permeability, and suppressing tumor cell migration [PMID:29965781, PMID:33731709]. RAB26 localizes to secretory granule membranes and to LAMP1/cathepsin D-positive lysosomes, driving lysosome coalescence and influencing organelle positioning [PMID:10857477, PMID:24413166], and it controls regulated secretion: it restrains cAMP-dependent granule exocytosis [PMID:16076461] and directly binds the synaptotagmin-1 C2A domain to disrupt the Syt1–SNAP25 interaction and limit insulin granule exocytosis [PMID:37289842]. RAB26 separately governs anterograde Golgi-to-surface transport of multiple receptors through activation-dependent binding—of α2-adrenergic receptors, EPOR, and AT1R—shaping adrenergic signaling, macrophage polarization, and hypoxic vascular remodeling [PMID:23105096, PMID:34925338, PMID:41231254]. It also protects mitochondrial integrity by binding VDAC1 to block its oligomerization and by regulating MFN2 delivery, thereby restraining cGAS-STING activation and ferroptosis [PMID:42176907, PMID:37060270]. RAB26 transcription is activated by MIST1 in secretory zymogenic cells, where it is required for large secretory granule formation [PMID:20038531], and by SMAD3 and KLF4 in cancer contexts [PMID:35291909, PMID:37431852], while ROS/cigarette-smoke-driven DNMT3b promoter hypermethylation suppresses its expression [PMID:36610560].","teleology":[{"year":2000,"claim":"Establishing that Rab26 is a bona fide GTP-binding protein resident on secretory granule membranes placed it in the regulated secretion machinery rather than a generic cytosolic GTPase.","evidence":"GTP-binding assay, subcellular fractionation, and immuno-EM in parotid acinar cells","pmids":["10857477"],"confidence":"Medium","gaps":["Effectors and GEF/GAP regulators not identified","Functional consequence of granule localization not yet tested"]},{"year":2005,"claim":"Antibody-inhibition in permeabilized acinar cells showed Rab26 selectively supports cAMP-dependent, not Ca2+-dependent, granule exocytosis, assigning it to a specific secretory recruitment step.","evidence":"Antibody inhibition of amylase release in streptolysin-O-permeabilized parotid acinar cells with agonist-specificity","pmids":["16076461"],"confidence":"Medium","gaps":["Molecular partners mediating cAMP-selective recruitment unknown","Single lab, single tissue"]},{"year":2009,"claim":"Identifying RAB26 as a direct MIST1 transcriptional target and a requirement for secretory granule biogenesis connected its expression program to secretory cell differentiation.","evidence":"ChIP/EMSA of MIST1 at promoter E-boxes plus dominant-negative and prenylation-inhibitor granule-formation assays in zymogenic cells","pmids":["20038531"],"confidence":"High","gaps":["How RAB26 mechanistically builds large granules not resolved","Effector for granule formation not identified"]},{"year":2012,"claim":"Demonstrating activation-dependent binding to the α2B-AR third intracellular loop and Golgi arrest upon RAB26 loss revealed a distinct role in anterograde receptor trafficking beyond secretion.","evidence":"Mutant overexpression, siRNA, surface receptor quantification, and GTP-dependent pulldown in cell lines","pmids":["23105096"],"confidence":"High","gaps":["Whether trafficking and autophagy functions use distinct effectors unclear","Generality across other GPCRs not established at this stage"]},{"year":2014,"claim":"Showing RAB26 associates with lysosomes and drives their perinuclear coalescence and mitochondrial repositioning expanded its remit to organelle clustering and positioning.","evidence":"Fluorescence co-localization with lysosomal/granule markers and transfection in differentiating zymogenic cells","pmids":["24413166"],"confidence":"Medium","gaps":["Motor/tethering machinery for clustering not identified","Causal basis of mitochondrial redistribution unknown"]},{"year":2015,"claim":"Identifying ATG16L1 as a GTP-dependent direct effector that routes vesicles into preautophagosomal structures defined the core molecular mechanism of RAB26-mediated selective autophagy.","evidence":"Active vs GDP-preferring mutant overexpression in neurons, autophagy-marker co-localization, and direct effector binding assay","pmids":["25643395"],"confidence":"High","gaps":["Cargo selectivity determinants not fully defined","GEF activating RAB26 for this step unknown"]},{"year":2018,"claim":"Linking the RAB26–ATG16L1 axis to autophagic degradation of phospho-SRC and adherens-junction stability gave the autophagy function a defined substrate and an in vivo vascular phenotype.","evidence":"RAB26 KO mice permeability assays, reciprocal Co-IP with ATG16L1, and phospho-SRC/phospho-CDH5 westerns in endothelial cells","pmids":["29965781"],"confidence":"High","gaps":["How active SRC is selected as autophagic cargo unresolved","Direct vs indirect SRC engagement not distinguished"]},{"year":2019,"claim":"Placing RAB26 downstream of SNRPB splicing regulation and as a tumorigenicity modifier introduced post-transcriptional control of RAB26 levels in cancer.","evidence":"SNRPB siRNA, RT-PCR of intron-7 retention/NMD, and RAB26 re-expression rescue in NSCLC","pmids":["31511502"],"confidence":"Medium","gaps":["RAB26 effector mediating tumorigenicity not identified","Single lab"]},{"year":2020,"claim":"Showing the Coxiella effector CvpF hijacks RAB26 to recruit LC3B to bacterial vacuoles demonstrated that pathogens subvert RAB26-dependent autophagy for virulence.","evidence":"Transposon screen, CvpF–RAB26 pulldown, LC3B recruitment assay, and SCID mouse virulence model","pmids":["32116095"],"confidence":"Medium","gaps":["Whether CvpF acts as a GEF/GAP mimic or effector competitor unknown","Structural basis of CvpF–RAB26 binding undefined"]},{"year":2021,"claim":"Extending the SRC-autophagy mechanism to breast cancer migration, and defining EPOR surface trafficking for macrophage polarization, generalized RAB26's roles across autophagy and receptor delivery.","evidence":"Co-IP with ATG16L1 and migration assays in breast cancer cells; RAB26 KO mice and surface EPOR/M1-M2 polarization assays in macrophages","pmids":["33731709","34925338"],"confidence":"Medium","gaps":["Whether EPOR trafficking uses the same effector machinery as GPCRs unclear","Direct RAB26–EPOR interaction not demonstrated here"]},{"year":2022,"claim":"Multiple 2022 studies anchored RAB26 in transcriptional networks (SMAD3, KLF4), redox-driven epigenetic silencing (DNMT3b), conserved granule-maturation control in Drosophila, and α-synuclein-sensitive synaptic autophagy.","evidence":"ChIP/luciferase for SMAD3 and KLF4; promoter methylation and MAPK readouts for ROS/DNMT3b; Drosophila Rab26/Mon1 epistasis; α-synuclein shRNA rescue of Rab26-ATG16L1 co-localization in neurons","pmids":["35291909","37431852","36610560","36600084","36341850"],"confidence":"Medium","gaps":["How divergent transcriptional inputs are integrated unknown","Mechanism by which α-synuclein disrupts the RAB26-ATG16L1 interface undefined"]},{"year":2023,"claim":"Direct binding to synaptotagmin-1 C2A and to mitochondrial MFN2 broadened RAB26 from a trafficking GTPase to a regulator of exocytic priming and mitochondrial function.","evidence":"GST pulldown with Syt1 C2A, KO mice and TIRF insulin-granule imaging; Co-IP with MFN2, KO macrophages and mitochondrial ROS/ATP/phagocytosis assays","pmids":["37289842","37060270"],"confidence":"High","gaps":["Whether Syt1 sequestration is GTP-dependent not fully resolved","How MFN2 transport is mechanistically coupled to RAB26 unknown"]},{"year":2025,"claim":"Defining RAB26 control of AT1R surface transport in hypoxic vascular remodeling and SERT autophagic degradation in neurons connected RAB26 to disease-relevant receptor homeostasis and behavior.","evidence":"Co-IP and KO mice in PAH model (AT1R/STAT3/YAP1); KO mice with behavioral, electrophysiological and EM analyses plus Co-IP with SERT","pmids":["41231254","40687824"],"confidence":"Medium","gaps":["Whether AT1R and SERT use the same trafficking machinery unclear","Direct effector bridging RAB26 to these receptors not defined"]},{"year":2026,"claim":"Identifying RAB26 binding to VDAC1 to block oligomerization and stabilization of EPOR against BTRC-mediated degradation tied RAB26 to suppression of ferroptosis and cGAS-STING signaling.","evidence":"Co-IP and cross-linking with VDAC1, TEM, KO mice and STING inhibition; Co-IP of BTRC-EPOR, KO macrophages and ferroptosis/mitophagy assays in sepsis models","pmids":["42176907","42086108"],"confidence":"Medium","gaps":["Whether VDAC1 and EPOR functions are mechanistically related unknown","Single lab for each axis"]},{"year":null,"claim":"How a single GTPase coordinates the choice among selective autophagy, anterograde receptor delivery, secretory granule control, and mitochondrial protection—and which GEFs, GAPs, and effectors switch between these programs—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of RAB26 with ATG16L1 or receptor partners","Upstream GEF/GAP regulators largely unidentified","Determinants selecting distinct cargo/effectors across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,14,21]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5,20]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[15,21]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,6,16]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4,10,18]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,10,18]}],"complexes":[],"partners":["ATG16L1","SYT1","ADRA2B","EPOR","MFN2","VDAC1","AGTR1","SLC6A4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULW5","full_name":"Ras-related protein Rab-26","aliases":[],"length_aa":256,"mass_kda":27.9,"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 set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (By similarity). RAB26 mediates transport of ADRA2A and ADRA2B from the Golgi to the cell membrane (PubMed:23105096). Plays a role in the maturation of zymogenic granules and in pepsinogen secretion in the stomach (PubMed:20038531). Plays a role in the secretion of amylase from acinar granules in the parotid gland (By similarity)","subcellular_location":"Golgi apparatus membrane; Cytoplasmic vesicle, secretory vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULW5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB26","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RAB26","total_profiled":1310},"omim":[{"mim_id":"620890","title":"GROWTH HORMONE-REGULATED TBC PROTEIN 1; GRTP1","url":"https://www.omim.org/entry/620890"},{"mim_id":"609956","title":"RAS-ASSOCIATED PROTEIN RAB37; RAB37","url":"https://www.omim.org/entry/609956"},{"mim_id":"605455","title":"RAS-ASSOCIATED PROTEIN RAB26; RAB26","url":"https://www.omim.org/entry/605455"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Centrosome","reliability":"Uncertain"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":116.2},{"tissue":"liver","ntpm":51.4},{"tissue":"pancreas","ntpm":41.6}],"url":"https://www.proteinatlas.org/search/RAB26"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9ULW5","domains":[{"cath_id":"3.40.50.300","chopping":"61-230_237-250","consensus_level":"high","plddt":89.8048,"start":61,"end":250}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULW5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULW5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULW5-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB26","jax_strain_url":"https://www.jax.org/strain/search?query=RAB26"},"sequence":{"accession":"Q9ULW5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULW5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULW5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULW5"}},"corpus_meta":[{"pmid":"25643395","id":"PMC_25643395","title":"The 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(GTP-bound/active form) specifically associates with clusters of synaptic vesicles in neurites and directs synaptic and secretory vesicles into preautophagosomal structures co-localizing with Atg16L1, LC3B, and Rab33B. Atg16L1 was identified as a direct effector of Rab26, binding selectively to the GTP-bound form of Rab26.\",\n      \"method\": \"Overexpression of active vs. GDP-preferring Rab26 mutants in neurons, co-localization with autophagy markers, direct binding assay (Atg16L1 as effector)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional mutant analysis, direct effector binding demonstrated, replicated across multiple cell systems and later by independent labs\",\n      \"pmids\": [\"25643395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RAB26 is a direct transcriptional target of the transcription factor MIST1, which binds conserved CATATG E-boxes in the RAB26 promoter to activate its transcription. RAB26 activity (alongside RAB3D) is required for the formation of large secretory granules in gastric zymogenic cells; dominant-negative RAB26 and RAB prenylation inhibitors abrogate granule formation.\",\n      \"method\": \"ChIP/EMSA showing MIST1 binding to RAB26 E-boxes; dominant-negative RAB26 transfection; RAB prenylation inhibitor treatment; RFP-pepsinogen C granule formation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter binding demonstrated, loss-of-function with dominant-negative and chemical inhibitor, specific granule formation phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"20038531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Rab26 protein localizes specifically to secretory granule membranes in parotid acinar cells, binds GTP, and its immunostaining disappears after isoproterenol treatment, consistent with a role in regulated secretory granule exocytosis.\",\n      \"method\": \"Western blotting with GTP-binding assay ([α-32P]GTP), subcellular fractionation, immunocytochemistry (light and electron microscopy)\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct GTP-binding demonstrated, subcellular fractionation and EM localization, single lab\",\n      \"pmids\": [\"10857477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Rab26 localizes to mature (not immature) secretory granule membranes in parotid acinar cells. Anti-Rab26 antibody inhibits isoproterenol (β-adrenergic/cAMP)-induced amylase release from permeabilized acinar cells but has no effect on Ca2+-induced amylase release, indicating a selective role in cAMP-dependent granule recruitment to the plasma membrane.\",\n      \"method\": \"Percoll-sucrose density gradient fractionation; antibody inhibition of exocytosis in streptolysin-O-permeabilized acinar cells; amylase secretion assay\",\n      \"journal\": \"Archives of oral biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional antibody-inhibition assay in permeabilized cells with specific agonist selectivity, single lab\",\n      \"pmids\": [\"16076461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rab26 regulates anterograde transport of α2A- and α2B-adrenergic receptors from the Golgi to the cell surface. Rab26 mutants and siRNA-mediated knockdown arrest receptors in the Golgi and reduce cell surface receptor numbers. Rab26 directly and activation-dependently interacts with the third intracellular loop of α2B-AR.\",\n      \"method\": \"Rab26 mutant overexpression and siRNA knockdown; cell surface receptor quantification; co-immunoprecipitation/pulldown demonstrating direct GTP-dependent interaction with α2B-AR third intracellular loop\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct GTP-dependent binding shown, Golgi arrest phenotype with two independent loss-of-function approaches (mutant + siRNA), functional ERK1/2 readout\",\n      \"pmids\": [\"23105096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RAB26 associates predominantly with LAMP1/cathepsin D-positive lysosomes (not secretory granules) and drives lysosome coalescence into a central perinuclear region. Lysosome clustering caused by increased RAB26 expression in turn redistributes mitochondria into distinct subcellular neighborhoods.\",\n      \"method\": \"Fluorescence co-localization with lysosomal and secretory granule markers; induction of zymogen-secreting cell differentiation; direct transfection of RAB26\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct subcellular localization with functional consequence (lysosome clustering, mitochondria redistribution), single lab, two induction approaches\",\n      \"pmids\": [\"24413166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAB26 promotes autophagic degradation of phosphorylated (active) SRC kinase in endothelial cells through direct, GTP-dependent interaction with ATG16L1. Loss of RAB26 leads to SRC phosphorylation, CDH5/VE-cadherin phosphorylation, CDH5 internalization, and disruption of adherens junctions, increasing vascular permeability in acute lung injury.\",\n      \"method\": \"RAB26 knockout mice (vascular permeability assays), siRNA depletion and overexpression in HPMECs, co-immunoprecipitation of RAB26 with ATG16L1 (GTP-dependent), western blot for phospho-SRC and phospho-CDH5\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo KO with defined permeability phenotype, overexpression rescue, consistent with prior ATG16L1 effector finding from independent lab\",\n      \"pmids\": [\"29965781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAB26 is a critical target of SNRPB-mediated splicing regulation in NSCLC; SNRPB depletion causes intron 7 retention in RAB26 mRNA, triggering nonsense-mediated decay (NMD) and reducing RAB26 protein levels. Forced RAB26 re-expression partially rescues decreased tumorigenicity caused by SNRPB depletion.\",\n      \"method\": \"siRNA knockdown of SNRPB; RT-PCR demonstrating intron retention; NMD pathway analysis; RAB26 re-expression rescue assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — splicing mechanism demonstrated by RT-PCR, rescue experiment confirms functional link, single lab\",\n      \"pmids\": [\"31511502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The Coxiella burnetii effector protein CvpF specifically interacts with host RAB26, recruiting the autophagosomal marker LC3B to Coxiella-containing vacuoles, thereby subverting RAB26-dependent autophagy to promote vacuole biogenesis and bacterial virulence.\",\n      \"method\": \"Transposon mutant library screen; co-immunoprecipitation/pulldown of CvpF with RAB26; LC3B recruitment assay; SCID mouse virulence model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction shown, functional consequence in vacuole biogenesis and in vivo virulence, single lab\",\n      \"pmids\": [\"32116095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab26 mediates autophagic degradation of phosphorylated Src kinase in breast cancer cells through interaction with ATG16L1. Rab26 promotes endosomal translocation of Src and reduces Src at focal adhesions, thereby suppressing cell migration and invasion.\",\n      \"method\": \"Rab26 overexpression and knockdown; immunofluorescence co-localization of Src with endosomal markers; Co-IP with ATG16L1; migration/invasion assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with ATG16L1, subcellular redistribution of Src shown, functional phenotype in migration/invasion, single lab\",\n      \"pmids\": [\"33731709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab26 regulates cell surface transport of the erythropoietin receptor (EPOR) in macrophages; loss of Rab26 reduces surface EPOR levels, impairs EPO-mediated M2 macrophage polarization, and tips macrophage phenotype toward M1.\",\n      \"method\": \"Rab26 KO mice; macrophage polarization assays; cell surface EPOR measurement after Rab26 modulation\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined polarization phenotype, EPOR surface levels quantified, single lab\",\n      \"pmids\": [\"34925338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMAD3 transcriptionally activates RAB26 by binding to the RAB26 promoter, as demonstrated by dual-luciferase reporter and chromatin immunoprecipitation assays. SMAD3 overexpression blocks inhibitory effects of RAB26 silencing on NSCLC cell proliferation, migration, and invasion.\",\n      \"method\": \"Dual-luciferase reporter assay; chromatin immunoprecipitation (ChIP); RAB26 shRNA knockdown; SMAD3 overexpression rescue\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP and luciferase reporter, functional rescue, single lab\",\n      \"pmids\": [\"35291909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila salivary glands, Rab26 localizes to immature secretory glue granules and prevents their acidification and premature maturation. Rab26 loss accelerates granule maturation, acidification, fusion, and lysosomal breakdown (crinophagy). Loss of Mon1 (an activator of Rab7) causes Rab26 to remain on large granules, implicating a Mon1-Rab7 pathway that counteracts Rab26 to drive granule maturation.\",\n      \"method\": \"Rab26 mutant Drosophila; fluorescence microscopy of glue granule acidification and fusion; genetic epistasis with Mon1 mutant; overexpression studies\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined granule maturation phenotype, epistasis with Mon1, Drosophila ortholog\",\n      \"pmids\": [\"36600084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Manganese-induced α-synuclein overexpression suppresses Rab26-ATG16L1 co-localization and reduces LC3II-positive synaptic vesicles, impairing Rab26-dependent autophagy initiation and causing accumulation of dysfunctional synaptic vesicles. Knockdown of α-synuclein with shRNA restores Rab26-ATG16L1 co-localization in Mn-exposed neurons.\",\n      \"method\": \"α-synuclein shRNA knockdown in primary hippocampal neurons; co-localization of Rab26 with ATG16L1 and LC3II-positive SVs by immunofluorescence; in vivo Mn exposure mouse model\",\n      \"journal\": \"The Science of the total environment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic rescue with shRNA showing restored Rab26-ATG16L1 co-localization, in vivo and in vitro concordance, single lab\",\n      \"pmids\": [\"36341850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rab26 directly interacts with synaptotagmin-1 (Syt1) via the Syt1 C2A domain (shown by GST pulldown), interfering with Syt1-SNAP25 interaction and inhibiting exocytosis of newcomer insulin granules. Rab26 knockout mice show increased glucose-stimulated insulin secretion, and Rab26 overexpression in islets suppresses insulin secretion; Rab26 overexpression causes clustering of insulin granules.\",\n      \"method\": \"Rab26-/- mice (CRISPR/Cas9); GST pulldown of Rab26 with Syt1 C2A domain; TIRF microscopy of insulin granule exocytosis; Rab26 KD in insulinoma cells; islet transplantation assay\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct in vitro binding assay, KO mouse with physiological phenotype, TIRF single-granule imaging, multiple orthogonal methods in one study\",\n      \"pmids\": [\"37289842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rab26 interacts with mitochondrial fusion protein MFN2 and regulates MFN2 transport to mitochondria. Rab26 deficiency reduces mitochondrial MFN2 levels, decreases mitochondrial ROS and ATP production, and impairs macrophage phagocytosis and bacterial clearance.\",\n      \"method\": \"Co-immunoprecipitation of Rab26 with MFN2; Rab26 KO bone marrow-derived macrophages; MFN2 siRNA knockdown; mitochondrial ROS and ATP measurement; phagocytosis/bacterial killing assays; in vivo ARDS mouse model\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, KO with defined mitochondrial and phagocytosis phenotype, siRNA epistasis, single lab\",\n      \"pmids\": [\"37060270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KLF4 transcriptionally targets RAB26 (verified by luciferase reporter assay) to inhibit autophagy in colon cancer cells. KLF4 overexpression suppresses LC3II/I ratio and autophagosome formation; RAB26 knockdown or rapamycin treatment reverses this effect and restores 5-FU resistance.\",\n      \"method\": \"Luciferase reporter assay for KLF4-RAB26 promoter interaction; RAB26 shRNA knockdown; autophagosome imaging by confocal microscopy; 5-FU resistance assay; xenograft mouse model\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct promoter interaction by luciferase assay, genetic rescue epistasis, single lab\",\n      \"pmids\": [\"37431852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ROS/cigarette smoke exposure induces DNMT3b-mediated hypermethylation of the Rab26 promoter, suppressing Rab26 expression. Reduced Rab26 activates p38 and JNK MAPK signaling to promote airway epithelial inflammatory mediator production; Rab26 overexpression attenuates this response.\",\n      \"method\": \"Rab26 promoter methylation assay; DNMT3b siRNA; antioxidant (NAC) and DNA methylation inhibitor (5-AZA) treatment; Rab26 overexpression/silencing with p38/JNK phosphorylation readouts; in vivo smoking mouse model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — promoter methylation mechanism validated, MAPK pathway placement by OE/KD, multiple in vitro and in vivo approaches, single lab\",\n      \"pmids\": [\"36610560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rab26 interacts with angiotensin II Type 1 receptor (AT1R) and promotes its transport to the cell surface in pulmonary artery smooth muscle cells (PASMCs), thereby activating STAT3 and upregulating/promoting nuclear translocation of YAP1, driving PASMC hyper-proliferation under hypoxia.\",\n      \"method\": \"Co-immunoprecipitation of Rab26 with AT1R; Rab26 KO mice (PAH model); pharmacological inhibition of AT1R and pSTAT3; assessment of pSTAT3 and YAP1 levels; pulmonary vascular remodeling histology\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP interaction, KO mouse with vascular remodeling phenotype, pharmacological epistasis, single lab\",\n      \"pmids\": [\"41231254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rab26 deficiency in mice causes depression/anxiety-like behaviors and cognitive impairment. Mechanistically, Rab26 interacts with the serotonin transporter SERT and promotes its autophagic degradation; loss of Rab26 increases cell surface SERT levels, reduces synaptic vesicle turnover (accumulation of SVs at presynaptic terminals), and decreases mEPSC frequency and LTP.\",\n      \"method\": \"Rab26-/- mice; behavioral tests; co-immunoprecipitation of Rab26 with SERT; cell surface SERT measurement; electrophysiology (mEPSC, LTP); electron microscopy of SV accumulation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, KO mouse with multiple orthogonal phenotypes (behavioral, electrophysiological, ultrastructural), single lab\",\n      \"pmids\": [\"40687824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rab26 facilitates lysosomal translocation and degradation of eukaryotic elongation factor 1A (eEF1A) in cardiomyocytes. Cardiac-specific Rab26 overexpression (via AAV9) reduces eEF1A levels, improving cardiac function and reducing hypertrophy; eEF1A silencing eliminates the cardioprotective effect of Rab26.\",\n      \"method\": \"Protein interaction studies (Co-IP/pulldown); fluorescence co-localization of Rab26 and eEF1A with lysosomes; protease inhibition assays; AAV9-cardiac-specific Rab26 overexpression; Rab26 KO; TAC mouse model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction, lysosomal co-localization with protease inhibition confirmation, epistasis via eEF1A silencing, KO and OE mouse models, single lab\",\n      \"pmids\": [\"40609824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Rab26 physically binds to mitochondrial VDAC1 and prevents its oligomerization. Loss of Rab26 promotes VDAC1 oligomerization, mitochondrial membrane permeabilization, and mtDNA leakage into the cytosol, which hyperactivates cGAS-STING signaling, represses SLC7A11/GPX4, and drives ferroptosis in airway epithelial cells exposed to cigarette smoke.\",\n      \"method\": \"Co-immunoprecipitation; chemical cross-linking; transmission electron microscopy; Rab26-/- mice; pharmacological STING inhibition; GPX4/SLC7A11 western blot\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Rab26-VDAC1 interaction by Co-IP and cross-linking, TEM ultrastructure, KO mouse with in vivo phenotype, pharmacological epistasis, single lab\",\n      \"pmids\": [\"42176907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Rab26 stabilizes EPOR by preventing its ubiquitin-mediated proteasomal degradation; Rab26 deficiency upregulates the E3 ligase BTRC, which interacts with EPOR to promote EPOR degradation. This reduces EPOR levels, suppresses the PPARγ/GPX4 and PINK1-mediated mitophagy axes, and sensitizes macrophages to ferroptosis.\",\n      \"method\": \"Co-IP of BTRC with EPOR; Rab26 KO macrophages; EPOR and BTRC protein level measurement; PPARγ antagonism; mitophagy assays; ferroptosis (lipid peroxidation, GPX4) assays; CLP sepsis mouse model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP of BTRC-EPOR interaction, KO mouse with in vivo sepsis phenotype, pharmacological epistasis of PPARγ and PINK1 pathway, single lab\",\n      \"pmids\": [\"42086108\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB26 is a GTP-binding small GTPase that, in its active (GTP-bound) state, directly engages ATG16L1 as an effector to link synaptic/secretory vesicles and lysosomes to preautophagosomal structures for selective autophagic degradation; it also coordinates anterograde Golgi-to-plasma-membrane trafficking of multiple receptors (α2-adrenergic receptors, EPOR, AT1R), sequesters synaptotagmin-1 to restrain insulin granule exocytosis, interacts with VDAC1 to protect mitochondrial integrity, and is transcriptionally regulated by MIST1 (in secretory cells), SMAD3, and KLF4, with its expression suppressed by ROS-driven promoter hypermethylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB26 is a GTP-binding small GTPase that coordinates membrane trafficking and selective autophagy of secretory and synaptic vesicles, lysosomes, and surface receptors [#0, #14]. In its active GTP-bound state it engages ATG16L1 as a direct effector, routing synaptic and secretory vesicles into preautophagosomal structures marked by LC3B and Rab33B for autophagic degradation [#0]; this RAB26–ATG16L1 axis targets active phosphorylated SRC for degradation, thereby maintaining endothelial adherens junctions and limiting vascular permeability, and suppressing tumor cell migration [#6, #9]. RAB26 localizes to secretory granule membranes and to LAMP1/cathepsin D-positive lysosomes, driving lysosome coalescence and influencing organelle positioning [#2, #5], and it controls regulated secretion: it restrains cAMP-dependent granule exocytosis [#3] and directly binds the synaptotagmin-1 C2A domain to disrupt the Syt1–SNAP25 interaction and limit insulin granule exocytosis [#14]. RAB26 separately governs anterograde Golgi-to-surface transport of multiple receptors through activation-dependent binding—of \\u03b12-adrenergic receptors, EPOR, and AT1R—shaping adrenergic signaling, macrophage polarization, and hypoxic vascular remodeling [#4, #10, #18]. It also protects mitochondrial integrity by binding VDAC1 to block its oligomerization and by regulating MFN2 delivery, thereby restraining cGAS-STING activation and ferroptosis [#21, #15]. RAB26 transcription is activated by MIST1 in secretory zymogenic cells, where it is required for large secretory granule formation [#1], and by SMAD3 and KLF4 in cancer contexts [#11, #16], while ROS/cigarette-smoke-driven DNMT3b promoter hypermethylation suppresses its expression [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that Rab26 is a bona fide GTP-binding protein resident on secretory granule membranes placed it in the regulated secretion machinery rather than a generic cytosolic GTPase.\",\n      \"evidence\": \"GTP-binding assay, subcellular fractionation, and immuno-EM in parotid acinar cells\",\n      \"pmids\": [\"10857477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effectors and GEF/GAP regulators not identified\", \"Functional consequence of granule localization not yet tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Antibody-inhibition in permeabilized acinar cells showed Rab26 selectively supports cAMP-dependent, not Ca2+-dependent, granule exocytosis, assigning it to a specific secretory recruitment step.\",\n      \"evidence\": \"Antibody inhibition of amylase release in streptolysin-O-permeabilized parotid acinar cells with agonist-specificity\",\n      \"pmids\": [\"16076461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners mediating cAMP-selective recruitment unknown\", \"Single lab, single tissue\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying RAB26 as a direct MIST1 transcriptional target and a requirement for secretory granule biogenesis connected its expression program to secretory cell differentiation.\",\n      \"evidence\": \"ChIP/EMSA of MIST1 at promoter E-boxes plus dominant-negative and prenylation-inhibitor granule-formation assays in zymogenic cells\",\n      \"pmids\": [\"20038531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB26 mechanistically builds large granules not resolved\", \"Effector for granule formation not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating activation-dependent binding to the \\u03b12B-AR third intracellular loop and Golgi arrest upon RAB26 loss revealed a distinct role in anterograde receptor trafficking beyond secretion.\",\n      \"evidence\": \"Mutant overexpression, siRNA, surface receptor quantification, and GTP-dependent pulldown in cell lines\",\n      \"pmids\": [\"23105096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether trafficking and autophagy functions use distinct effectors unclear\", \"Generality across other GPCRs not established at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing RAB26 associates with lysosomes and drives their perinuclear coalescence and mitochondrial repositioning expanded its remit to organelle clustering and positioning.\",\n      \"evidence\": \"Fluorescence co-localization with lysosomal/granule markers and transfection in differentiating zymogenic cells\",\n      \"pmids\": [\"24413166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Motor/tethering machinery for clustering not identified\", \"Causal basis of mitochondrial redistribution unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying ATG16L1 as a GTP-dependent direct effector that routes vesicles into preautophagosomal structures defined the core molecular mechanism of RAB26-mediated selective autophagy.\",\n      \"evidence\": \"Active vs GDP-preferring mutant overexpression in neurons, autophagy-marker co-localization, and direct effector binding assay\",\n      \"pmids\": [\"25643395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo selectivity determinants not fully defined\", \"GEF activating RAB26 for this step unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking the RAB26–ATG16L1 axis to autophagic degradation of phospho-SRC and adherens-junction stability gave the autophagy function a defined substrate and an in vivo vascular phenotype.\",\n      \"evidence\": \"RAB26 KO mice permeability assays, reciprocal Co-IP with ATG16L1, and phospho-SRC/phospho-CDH5 westerns in endothelial cells\",\n      \"pmids\": [\"29965781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How active SRC is selected as autophagic cargo unresolved\", \"Direct vs indirect SRC engagement not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placing RAB26 downstream of SNRPB splicing regulation and as a tumorigenicity modifier introduced post-transcriptional control of RAB26 levels in cancer.\",\n      \"evidence\": \"SNRPB siRNA, RT-PCR of intron-7 retention/NMD, and RAB26 re-expression rescue in NSCLC\",\n      \"pmids\": [\"31511502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RAB26 effector mediating tumorigenicity not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing the Coxiella effector CvpF hijacks RAB26 to recruit LC3B to bacterial vacuoles demonstrated that pathogens subvert RAB26-dependent autophagy for virulence.\",\n      \"evidence\": \"Transposon screen, CvpF–RAB26 pulldown, LC3B recruitment assay, and SCID mouse virulence model\",\n      \"pmids\": [\"32116095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CvpF acts as a GEF/GAP mimic or effector competitor unknown\", \"Structural basis of CvpF–RAB26 binding undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending the SRC-autophagy mechanism to breast cancer migration, and defining EPOR surface trafficking for macrophage polarization, generalized RAB26's roles across autophagy and receptor delivery.\",\n      \"evidence\": \"Co-IP with ATG16L1 and migration assays in breast cancer cells; RAB26 KO mice and surface EPOR/M1-M2 polarization assays in macrophages\",\n      \"pmids\": [\"33731709\", \"34925338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EPOR trafficking uses the same effector machinery as GPCRs unclear\", \"Direct RAB26–EPOR interaction not demonstrated here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple 2022 studies anchored RAB26 in transcriptional networks (SMAD3, KLF4), redox-driven epigenetic silencing (DNMT3b), conserved granule-maturation control in Drosophila, and \\u03b1-synuclein-sensitive synaptic autophagy.\",\n      \"evidence\": \"ChIP/luciferase for SMAD3 and KLF4; promoter methylation and MAPK readouts for ROS/DNMT3b; Drosophila Rab26/Mon1 epistasis; \\u03b1-synuclein shRNA rescue of Rab26-ATG16L1 co-localization in neurons\",\n      \"pmids\": [\"35291909\", \"37431852\", \"36610560\", \"36600084\", \"36341850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How divergent transcriptional inputs are integrated unknown\", \"Mechanism by which \\u03b1-synuclein disrupts the RAB26-ATG16L1 interface undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Direct binding to synaptotagmin-1 C2A and to mitochondrial MFN2 broadened RAB26 from a trafficking GTPase to a regulator of exocytic priming and mitochondrial function.\",\n      \"evidence\": \"GST pulldown with Syt1 C2A, KO mice and TIRF insulin-granule imaging; Co-IP with MFN2, KO macrophages and mitochondrial ROS/ATP/phagocytosis assays\",\n      \"pmids\": [\"37289842\", \"37060270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Syt1 sequestration is GTP-dependent not fully resolved\", \"How MFN2 transport is mechanistically coupled to RAB26 unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining RAB26 control of AT1R surface transport in hypoxic vascular remodeling and SERT autophagic degradation in neurons connected RAB26 to disease-relevant receptor homeostasis and behavior.\",\n      \"evidence\": \"Co-IP and KO mice in PAH model (AT1R/STAT3/YAP1); KO mice with behavioral, electrophysiological and EM analyses plus Co-IP with SERT\",\n      \"pmids\": [\"41231254\", \"40687824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AT1R and SERT use the same trafficking machinery unclear\", \"Direct effector bridging RAB26 to these receptors not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identifying RAB26 binding to VDAC1 to block oligomerization and stabilization of EPOR against BTRC-mediated degradation tied RAB26 to suppression of ferroptosis and cGAS-STING signaling.\",\n      \"evidence\": \"Co-IP and cross-linking with VDAC1, TEM, KO mice and STING inhibition; Co-IP of BTRC-EPOR, KO macrophages and ferroptosis/mitophagy assays in sepsis models\",\n      \"pmids\": [\"42176907\", \"42086108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VDAC1 and EPOR functions are mechanistically related unknown\", \"Single lab for each axis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single GTPase coordinates the choice among selective autophagy, anterograde receptor delivery, secretory granule control, and mitochondrial protection—and which GEFs, GAPs, and effectors switch between these programs—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of RAB26 with ATG16L1 or receptor partners\", \"Upstream GEF/GAP regulators largely unidentified\", \"Determinants selecting distinct cargo/effectors across tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 14, 21]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5, 20]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 6, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4, 10, 18]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 10, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATG16L1\", \"SYT1\", \"ADRA2B\", \"EPOR\", \"MFN2\", \"VDAC1\", \"AGTR1\", \"SLC6A4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}