Affinage

RAB26

Ras-related protein Rab-26 · UniProt Q9ULW5

Length
256 aa
Mass
27.9 kDa
Annotated
2026-04-28
31 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAB26 is a small GTPase that functions as a versatile vesicle-trafficking regulator controlling secretory granule maturation, receptor transport, and selective autophagy. In its GTP-bound state, RAB26 directly binds ATG16L1 to recruit preautophagosomal machinery to synaptic vesicles, secretory granules, and specific cargo proteins—including phosphorylated SRC and the serotonin transporter SERT—targeting them for autophagic or lysosomal degradation (PMID:25643395, PMID:29965781, PMID:40687824, PMID:40609824). RAB26 also regulates Golgi-to-plasma-membrane trafficking of GPCRs (α2-adrenergic receptors, AT1R) through direct, activation-dependent interactions with receptor intracellular domains, and negatively regulates exocytosis by sequestering synaptotagmin-1's C2A domain to inhibit newcomer granule fusion (PMID:23105096, PMID:37289842, PMID:41231254). RAB26 transcription is controlled by MIST1 in secretory cell lineages and by SMAD3 in cancer cells, and in Drosophila secretory glands RAB26 prevents premature vesicle acidification, establishing a conserved role in secretory granule maturation (PMID:20038531, PMID:35291909, PMID:36600084).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 Medium

    The initial characterization established that RAB26 is a GTP-binding protein localized to secretory granule membranes whose abundance changes upon exocytic stimulation, implicating it in regulated exocytosis.

    Evidence GTP-binding assay, subcellular fractionation, and immunocytochemistry in parotid acinar cells with isoproterenol stimulation

    PMID:10857477

    Open questions at the time
    • No effector or binding partner identified
    • Mechanism of RAB26 disappearance upon stimulation unknown
    • Only one secretory cell type examined
  2. 2005 Medium

    Function-blocking antibody experiments revealed that RAB26 specifically mediates cAMP/β-adrenergic-stimulated (but not Ca²⁺-induced) exocytosis and associates selectively with mature secretory granules, establishing pathway selectivity.

    Evidence Percoll-sucrose fractionation and anti-Rab26 antibody in streptolysin-O-permeabilized acinar cells with secretagogue dissection

    PMID:16076461

    Open questions at the time
    • No downstream effector of RAB26 in exocytosis identified
    • Mechanism of mature-granule selectivity unknown
  3. 2009 High

    Identification of MIST1 as a direct transcriptional activator of RAB26 linked its expression to secretory cell differentiation and showed RAB26 is required for large secretory granule formation.

    Evidence ChIP for MIST1 at RAB26 promoter, Mist1−/− mouse model, dominant-negative RAB26, granule formation assay

    PMID:20038531

    Open questions at the time
    • Whether RAB26 acts on granule biogenesis versus maturation not resolved
    • Downstream effectors of RAB26 in granule formation unknown
  4. 2012 High

    Discovery that RAB26 directly interacts with GPCR intracellular loops in a GTP-dependent manner and regulates Golgi-to-surface receptor transport established RAB26 as a receptor trafficking regulator beyond classical secretory granule biology.

    Evidence Co-immunoprecipitation with α2B-AR, dominant-negative/constitutively active mutants, siRNA knockdown, receptor surface expression and ERK1/2 readout

    PMID:23105096

    Open questions at the time
    • Whether RAB26 regulates trafficking of GPCRs beyond adrenergic receptors not yet tested
    • Structural basis of receptor-RAB26 interaction unknown
  5. 2014 Medium

    Localization studies in differentiating zymogenic cells revealed that RAB26 predominantly associates with LAMP1-positive lysosomes and reorganizes lysosomal positioning, suggesting a lysosome-regulatory function distinct from direct granule association.

    Evidence Subcellular fractionation and immunofluorescence co-localization with LAMP1/cathepsin D in zymogenic cells

    PMID:24413166

    Open questions at the time
    • Apparent conflict with earlier granule-membrane localization not mechanistically resolved
    • Whether lysosomal coalescence is a direct or indirect consequence of RAB26 activity unclear
  6. 2015 High

    Identification of ATG16L1 as a direct GTP-dependent effector of RAB26 provided the mechanistic link between RAB26 and autophagy, showing that RAB26 selectively channels synaptic and secretory vesicles into the autophagosomal pathway.

    Evidence GTP-dependent binding assay for ATG16L1, co-localization with LC3B and Rab33B, overexpression of active/inactive RAB26 mutants in neurons

    PMID:25643395

    Open questions at the time
    • How RAB26-ATG16L1 interaction is regulated or terminated unknown
    • Whether this pathway operates in non-neuronal secretory cells not established
  7. 2018 High

    Extending the autophagy function to a specific substrate, RAB26 was shown to target phosphorylated SRC for autophagic degradation via ATG16L1, with loss of RAB26 in knockout mice causing vascular permeability defects through VE-cadherin disruption.

    Evidence Rab26 knockout mice, siRNA in HPMECs, co-IP of SRC with LC3-II, phospho-SRC degradation assay, lung permeability measurement

    PMID:29965781

    Open questions at the time
    • How RAB26 recognizes phospho-SRC as cargo not determined
    • Whether other kinases are similarly targeted unknown
  8. 2020 Medium

    The discovery that Coxiella burnetii effector CvpF hijacks host RAB26 to recruit LC3B to pathogen-containing vacuoles demonstrated that intracellular pathogens exploit RAB26's autophagy-recruiting function for their own replication.

    Evidence Transposon mutant screening, co-IP and co-localization of CvpF with RAB26 and LC3B, SCID mouse virulence model

    PMID:32116095

    Open questions at the time
    • Whether CvpF mimics endogenous RAB26 effectors or acts through a distinct mechanism not resolved
    • Host cell type specificity not explored
  9. 2023 High

    Three studies collectively expanded RAB26's functional repertoire: direct binding to synaptotagmin-1's C2A domain explained negative regulation of insulin exocytosis, Drosophila genetics established a conserved role in preventing premature granule acidification, and MFN2 interaction linked RAB26 to mitochondrial biology.

    Evidence GST pulldown of Syt1 C2A domain and CRISPR KO mice with TIRF imaging (PMID:37289842); Drosophila Rab26 mutants with live granule imaging and Mon1 epistasis (PMID:36600084); co-IP of Rab26 with MFN2 and KO macrophages with mitochondrial readouts (PMID:37060270)

    PMID:36600084 PMID:37060270 PMID:37289842

    Open questions at the time
    • Whether Syt1 sequestration and autophagy functions are coordinated or context-specific unknown
    • Structural basis of Rab26-MFN2 interaction not determined
    • How Rab26 prevents granule acidification mechanistically remains unclear
  10. 2025 Medium

    Recent studies extended RAB26's receptor trafficking role to AT1R and SERT, linking RAB26 to pulmonary hypertension and depression-related neurotransmission, and identified eEF1A as a lysosomal degradation substrate mediating cardioprotection.

    Evidence Co-IP of Rab26 with AT1R and trafficking assays in PAH model (PMID:41231254); co-IP of Rab26 with SERT and KO mouse electrophysiology/behavior (PMID:40687824); cardiac Rab26 OE/KO with eEF1A degradation assay and TAC model (PMID:40609824)

    PMID:40609824 PMID:40687824 PMID:41231254

    Open questions at the time
    • Each receptor/substrate interaction studied in a single lab and tissue context
    • How RAB26 distinguishes between trafficking-to-surface and trafficking-to-autophagy outcomes for different cargoes is unknown
    • No unified structural model for RAB26's diverse cargo recognition

Open questions

Synthesis pass · forward-looking unresolved questions
  • A central unresolved question is how RAB26 mechanistically switches between promoting forward secretory trafficking versus directing cargo to autophagy/lysosomes, and whether distinct effector complexes or post-translational modifications control this cargo-sorting decision.
  • No structural data for RAB26 in complex with any effector
  • GEF and GAP for RAB26 not definitively identified in mammals
  • No systematic interactome distinguishing trafficking versus autophagy effector pools

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0031410 cytoplasmic vesicle 4 GO:0005764 lysosome 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-9612973 Autophagy 5 R-HSA-162582 Signal Transduction 2
Partners
ADRA2BAGTR1ATG16L1EEF1A1MFN2SLC6A4SRCSYT1

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Rab26 (GTP-bound active form) directly binds ATG16L1, linking synaptic vesicle clusters to preautophagosomal structures and selectively directing synaptic/secretory vesicles into autophagy pathway; both endogenous and induced vesicle clusters co-localize with Atg16L1, LC3B, and Rab33B but not other organelles. Overexpression of active/GDP-preferring Rab26 mutants in neurons, co-localization with autophagy markers, direct binding assay (ATG16L1 as effector in GTP-dependent manner), live imaging of vesicle clustering eLife High 25643395
2012 Rab26 regulates Golgi-to-cell-surface transport of α2A- and α2B-adrenergic receptors through a direct, GTP-activation-dependent physical interaction with the third intracellular loop of α2B-AR; dominant-negative Rab26 mutants and siRNA knockdown cause receptor retention in the Golgi and reduced cell surface numbers. siRNA knockdown, dominant-negative/constitutively active mutant expression, co-immunoprecipitation, receptor trafficking assays, ERK1/2 activation readout The Journal of biological chemistry High 23105096
2009 MIST1 transcription factor directly binds conserved CATATG E-boxes in the RAB26 promoter to activate RAB26 transcription, and RAB26 (along with RAB3D) is required for the formation of large secretory granules in gastric zymogenic cells; dominant-negative RAB26 and RAB prenylation inhibition abrogate granule formation. ChIP for MIST1 binding to RAB26 promoter, Mist1-/- mouse model showing RAB26 downregulation, transfection of dominant-negative RAB26, RFP-pepsinogen C granule formation assay in MIST1-expressing cancer cell lines Molecular and cellular biology High 20038531
2014 RAB26 predominantly associates with LAMP1/cathepsin D-positive lysosomes (not directly with secretory granules) and increasing RAB26 expression causes lysosomes to coalesce in a central perinuclear region, which in turn redistributes mitochondria into distinct subcellular neighborhoods. Subcellular fractionation, immunofluorescence co-localization with LAMP1/cathepsin D, direct transfection of RAB26 with organelle marker co-localization, differentiation of zymogen-secreting cells Journal of cell science Medium 24413166
2000 Rab26 is localized immediately around secretory granule membranes in parotid acinar cells, binds GTP, and its immunostaining disappears from acinar cells after isoproterenol treatment, suggesting participation in regulated secretory granule exocytosis. Western blotting with [α-32P]GTP binding assay, subcellular fractionation of secretory granule membranes, light and electron microscopic immunocytochemistry, isoproterenol stimulation Histochemistry and cell biology Medium 10857477
2005 Rab26 is present specifically in mature (not immature) secretory granule membrane fractions in parotid acinar cells, and an anti-Rab26 antibody inhibits isoproterenol (β-adrenergic)-induced but not Ca2+-induced amylase release, indicating Rab26 participates specifically in cAMP/β-adrenergic-stimulated granule recruitment to the plasma membrane. Percoll-sucrose density gradient centrifugation for granule fractionation, function-blocking antibody in streptolysin-O-permeabilized acinar cells, amylase secretion assay Archives of oral biology Medium 16076461
2018 RAB26 promotes autophagic degradation of phosphorylated SRC in endothelial cells through GTP-dependent interaction with ATG16L1; loss of RAB26 leads to accumulation of phospho-SRC, increased CDH5/VE-cadherin phosphorylation and internalization, and disruption of adherens junctions, increasing vascular permeability. Rab26 knockout mice, siRNA knockdown in HPMECs, RAB26 overexpression, co-immunoprecipitation of SRC with LC3-II, phospho-SRC degradation assay, VE-cadherin phosphorylation/internalization readout, lung permeability measurement Autophagy High 29965781
2021 Rab26 mediates autophagic degradation of phosphorylated Src in breast cancer cells through interaction with ATG16L1; Rab26 reduces focal adhesion association of Src, induces endosomal translocation of Src, and consequently suppresses cell migration and invasion. Rab26 overexpression and knockdown in breast cancer cells, co-immunoprecipitation with ATG16L1, fluorescence co-localization of Src with endosomal markers, migration/invasion assays Cell death & disease Medium 33731709
2019 SNRPB regulates RAB26 expression post-transcriptionally: SNRPB suppression causes intron 7 retention in RAB26 mRNA and consequent nonsense-mediated RNA decay (NMD)-mediated mRNA degradation, reducing RAB26 protein levels. SNRPB siRNA knockdown, RT-PCR to detect intron retention in RAB26 mRNA, NMD inhibition assays, rescue by RAB26 forced expression Cell death & disease Medium 31511502
2020 The Coxiella burnetii effector protein CvpF specifically interacts with host RAB26, and this interaction recruits the autophagosomal marker LC3B to Coxiella-containing vacuoles, promoting vacuole biogenesis and intracellular bacterial replication. Coxiella transposon mutant screening, co-localization of CvpF with RAB26 and LC3B, co-immunoprecipitation, SCID mouse virulence model Autophagy Medium 32116095
2023 Rab26 interacts with synaptotagmin-1 (Syt1) via direct binding to its C2A domain (shown by GST pulldown), which interferes with Syt1-SNAP25 interaction and inhibits newcomer insulin granule fusion with the plasma membrane, thereby acting as a negative regulator of insulin secretion in pancreatic β-cells. Rab26-/- mice (CRISPR/Cas9), Rab26 overexpression in insulinoma cell lines and isolated islets, GST-pulldown of Syt1 C2A domain, TIRF microscopy of newcomer insulin granule exocytosis, islet transplantation into diabetic mice PLoS biology High 37289842
2023 Rab26 localizes to immature (non-acidic) secretory glue granules in Drosophila salivary glands and prevents vesicle acidification; Rab26 mutation accelerates granule maturation, acidification, content reorganization, and release; loss of Mon1 (activator of Rab7) causes persistent Rab26 association with large granules and impaired glue release similar to Rab26 overexpression. Rab26 mutant Drosophila analysis, live imaging of glue granule acidification and release, genetic epistasis with Mon1 mutants, Rab26 overexpression phenotype characterization Cellular and molecular life sciences : CMLS High 36600084
2023 Rab26 interacts with mitofusin-2 (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. Rab26 knockout macrophages, co-immunoprecipitation of Rab26 with MFN2, MFN2 subcellular fractionation, MFN2 siRNA knockdown, mitochondrial ROS/ATP measurement, phagocytosis assay, in vivo mouse ARDS model The FEBS journal Medium 37060270
2022 SMAD3 directly binds the promoter of RAB26 and transcriptionally activates its expression, as demonstrated by dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP); SMAD3 overexpression rescues the inhibitory effects of RAB26 silencing on NSCLC cell proliferation and migration. Dual-luciferase reporter assay, ChIP assay for SMAD3 at RAB26 promoter, RAB26 shRNA knockdown, SMAD3 overexpression rescue experiments, A549 xenograft mouse model Bioengineered Medium 35291909
2025 Rab26 regulates trafficking of the serotonin transporter SERT/Slc6a4: Rab26 interacts with SERT and promotes its autophagic degradation; Rab26 deficiency leads to increased cell surface levels of SERT, accumulation of synaptic vesicles in presynaptic terminals, decreased mEPSC frequency and LTP, and depression/anxiety-like behaviors in mice. Rab26-/- mice, co-immunoprecipitation of Rab26 with SERT, cell surface biotinylation assay for SERT, electrophysiology (mEPSC, LTP), behavioral tests, immunofluorescence iScience Medium 40687824
2025 Rab26 facilitates lysosomal translocation and degradation of eEF1A (eukaryotic elongation factor 1A) in cardiomyocytes; cardiac-specific Rab26 overexpression reduces eEF1A, improves cardiac function, and suppresses myocardial hypertrophy; eEF1A silencing eliminates Rab26's cardioprotective effect, establishing the Rab26-eEF1A axis. Cardiac-specific Rab26 overexpression via AAV9, Rab26 knockout, transverse aortic constriction (TAC) model, protein interaction studies, fluorescence co-localization, protease inhibition assays, eEF1A siRNA rescue experiment Life sciences Medium 40609824
2025 Rab26 interacts with angiotensin II Type 1 receptor (AT1R) and modulates its transport to the cell surface, thereby activating STAT3, upregulating YAP1 expression, and promoting YAP1 nuclear translocation in pulmonary artery smooth muscle cells under hypoxia; Rab26 deficiency attenuates hypoxia-induced pulmonary vascular remodeling. Co-immunoprecipitation of Rab26 with AT1R, cell surface AT1R trafficking assay, Rab26 knockdown/knockout in rPASMCs and PAH mouse model, pSTAT3 and YAP1 measurements, pharmacological AT1R and STAT3 inhibition Cellular and molecular life sciences : CMLS Medium 41231254

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The GTPase Rab26 links synaptic vesicles to the autophagy pathway. eLife 149 25643395
2018 RAB26-dependent autophagy protects adherens junctional integrity in acute lung injury. Autophagy 102 29965781
2009 RAB26 and RAB3D are direct transcriptional targets of MIST1 that regulate exocrine granule maturation. Molecular and cellular biology 91 20038531
2019 SNRPB promotes the tumorigenic potential of NSCLC in part by regulating RAB26. Cell death & disease 53 31511502
2012 Rab26 modulates the cell surface transport of α2-adrenergic receptors from the Golgi. The Journal of biological chemistry 48 23105096
2014 RAB26 coordinates lysosome traffic and mitochondrial localization. Journal of cell science 44 24413166
2000 Expression, characterization, and localization of Rab26, a low molecular weight GTP-binding protein, in the rat parotid gland. Histochemistry and cell biology 41 10857477
2005 Relation of Rab26 to the amylase release from rat parotid acinar cells. Archives of oral biology 38 16076461
2020 Coxiella effector protein CvpF subverts RAB26-dependent autophagy to promote vacuole biogenesis and virulence. Autophagy 35 32116095
2017 Regulation on Toll-like Receptor 4 and Cell Barrier Function by Rab26 siRNA-loaded DNA Nanovector in Pulmonary Microvascular Endothelial Cells. Theranostics 30 28744333
2021 Rab26 suppresses migration and invasion of breast cancer cells through mediating autophagic degradation of phosphorylated Src. Cell death & disease 24 33731709
2021 Extracellular CIRP-Impaired Rab26 Restrains EPOR-Mediated Macrophage Polarization in Acute Lung Injury. Frontiers in immunology 21 34925338
2023 ROS induced the Rab26 promoter hypermethylation to promote cigarette smoking-induced airway epithelial inflammation of COPD through activation of MAPK signaling. Free radical biology & medicine 20 36610560
2023 KLF4 targets RAB26 and decreases 5-FU resistance through inhibiting autophagy in colon cancer. Cancer biology & therapy 19 37431852
2019 Targeted Delivery of Rab26 siRNA with Precisely Tailored DNA Prism for Lung Cancer Therapy. Chembiochem : a European journal of chemical biology 19 30610755
2022 Manganese-induced α-synuclein overexpression promotes the accumulation of dysfunctional synaptic vesicles and hippocampal synaptotoxicity by suppressing Rab26-dependent autophagy in presynaptic neurons. The Science of the total environment 17 36341850
2023 Rab26 promotes macrophage phagocytosis through regulation of MFN2 trafficking to mitochondria. The FEBS journal 11 37060270
2023 Rab26 alleviates sepsis-induced immunosuppression as a master regulator of macrophage ferroptosis and polarization shift. Free radical biology & medicine 11 38169213
2022 RAB26 contributes to the progression of non-small cell lung cancer after being transcriptionally activated by SMAD3. Bioengineered 11 35291909
2019 Endothelial Cell Inflammation and Barriers Are Regulated by the Rab26-Mediated Balance between β2-AR and TLR4 in Pulmonary Microvessel Endothelial Cells. Mediators of inflammation 11 31182932
2023 Rab26 restricts insulin secretion via sequestering Synaptotagmin-1. PLoS biology 10 37289842
2023 Rab26 controls secretory granule maturation and breakdown in Drosophila. Cellular and molecular life sciences : CMLS 8 36600084
2023 Targeting Rab26 to Conquer Cisplatin-Resistant Lung Cancer with Self-Assembled DNA Nanomaterials. Biomacromolecules 7 37010453
2023 A GCC repeat in RAB26 undergoes natural selection in human and harbors divergent genotypes in late-onset Alzheimer's disease. Gene 5 37931854
2000 cDNA cloning of a human RAB26-related gene encoding a Ras-like GTP-binding protein on chromosome 16p13.3 region. Journal of human genetics 5 11043516
2025 Targeting NAD + biosynthesis suppresses TGF-β1/Smads/RAB26 axis and potentiates cisplatin cytotoxicity in non-small cell lung cancer brain metastasis. Acta neuropathologica communications 1 40069888
2025 Rab26-mediated lysosomal translocation of eEF1A alleviates myocardial hypertrophy and cardiac remodeling. Life sciences 0 40609824
2025 Deficiency of Rab26 causes behavioral defects in mice through impaired trafficking of serotonin (5-HT) transporter. iScience 0 40687824
2025 RAB26 promotes prostate cancer progression via the MAPK/ERK-TWIST1 signaling axis. Genes & diseases 0 40821113
2025 Expression of the genes QPRT, RAB26, and SRPRB in cancer tissue from patients with triple-negative breast cancer as a biomarker for diagnosis, pharmacotherapy strategy, and survival: Evidence from bioinformatic database analysis. International journal of clinical pharmacology and therapeutics 0 40888212
2025 Rab26 promotes hypoxia-induced hyperproliferation of PASMCs by modulating the AT1R-STAT3-YAP axis. Cellular and molecular life sciences : CMLS 0 41231254