{"gene":"RAB11B","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2000,"finding":"RAB11B localizes to transferrin-positive recycling endosomes and is essential for recycling of internalized transferrin to the plasma membrane. Constitutively active (Q/L) and constitutively inactive (S/N) mutants both blocked transferrin recycling without affecting uptake; a prenylation-deficient mutant (ΔC) had no effect, indicating membrane association is required.","method":"GFP-tagged mutant overexpression, transferrin recycling assay, subcellular colocalization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean functional assay with multiple mutants in single lab, two orthogonal methods (colocalization + recycling assay)","pmids":["10942597"],"is_preprint":false},{"year":2003,"finding":"RAB11B in PC12 cells colocalizes with secretory vesicle markers. GDP-bound RAB11B stimulates constitutive secretion and depletes vesicular stores, while GTP-bound RAB11B directly impairs Ca2+-triggered exocytosis, demonstrating a GTP-dependent switch between regulated and constitutive secretory pathways in neuronal/neuroendocrine cells.","method":"Transfected hGH reporter in PC12 cells, constitutively active/inactive RAB11B mutants, secretion assays","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional exocytosis assay with GTP/GDP-locked mutants, single lab but multiple orthogonal readouts","pmids":["14627637"],"is_preprint":false},{"year":2003,"finding":"Endogenous RAB11B localizes to an apical pericentrisomal compartment distinct from RAB11A in polarized epithelial cells (MDCK and gastric parietal cells); its distribution is less dependent on microtubules than RAB11A, and it does not substantially colocalize with transferrin or IgA cargo handled by RAB11A.","method":"Immunofluorescence of endogenous proteins, nocodazole/taxol perturbation, subcellular fractionation/coisolation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional microtubule perturbation, single lab, multiple cell types","pmids":["14567990"],"is_preprint":false},{"year":2009,"finding":"RAB11B (but not RAB11A) selectively regulates apical recycling of CFTR in polarized intestinal epithelial (T84) cells. GDP-locked RAB11B-S25N inhibited ~80% of cAMP-activated halide efflux and reduced apical membrane CFTR by 50%; constitutively active RAB11B-Q70L increased stimulated efflux; RNAi knockdown of RAB11B (not RAB11A) reduced anion conductance by 50%.","method":"Dominant-negative/constitutively active mutant expression, RNAi knockdown, halide efflux assay, cell surface biotinylation, biotin protection recycling assay, immunoisolation of vesicles","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (dominant negative, constitutively active, RNAi, biotinylation, recycling protection assay) converging on same conclusion in single rigorous study","pmids":["19244346"],"is_preprint":false},{"year":2011,"finding":"RAB11B regulates apical recycling and surface expression of the epithelial sodium channel ENaC. Dominant-negative RAB11B (but not RAB11A) most effectively reduced basal and cAMP-stimulated ENaC-dependent Na+ transport; siRNA knockdown of RAB11B demonstrated its requirement for ENaC surface expression in mpkCCD cells.","method":"Dominant-negative mutant expression, siRNA knockdown, Ussing chamber Na+ transport assay, immunoisolation, confocal colocalization","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ion transport assays plus siRNA, single lab, multiple orthogonal methods","pmids":["22129970"],"is_preprint":false},{"year":2011,"finding":"RAB11B (not RAB11A) limits plasma membrane density of Cav1.2 L-type Ca2+ channels by promoting their degradation. Dominant-negative RAB11B-S25N or shRNA knockdown of RAB11B increased peak L-type Ba2+ current by ~64–66% and increased surface Cav1.2 density; cell surface biotinylation showed the effect is on degradation, not anterograde trafficking.","method":"Dominant-negative mutant, shRNA knockdown, whole-cell patch clamp, cell surface biotinylation, HA-tagged channel","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (dominant negative, shRNA, electrophysiology, biotinylation) in single lab","pmids":["21248079"],"is_preprint":false},{"year":2011,"finding":"RAB11B and its effector Rip11 regulate acidosis-induced trafficking of V-ATPase to the plasma membrane in salivary duct cells. RAB11B showed higher colocalization with V-ATPase than RAB11A; RAB11 (not RAB25) interacts with the ε subunit of V-ATPase; siRNA knockdown of RAB11B or Rip11 prevented acidosis-induced V-ATPase translocation.","method":"siRNA knockdown, confocal colocalization, co-immunoprecipitation (RAB11/V-ATPase ε subunit), immunofluorescence","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional siRNA knockdown, single lab, two orthogonal methods","pmids":["20717956"],"is_preprint":false},{"year":2012,"finding":"The cAMP/PKA/CREB signaling pathway controls acidosis-induced V-ATPase trafficking in salivary ducts via transcriptional regulation of RAB11B expression; PKA phosphorylates CREB which activates RAB11B transcription, and CREB loss-of-function downregulates RAB11B and impairs V-ATPase translocation.","method":"Pharmacological inhibitors/activators of PKA/Src/ERK, RT-PCR, immunoblotting, siRNA loss-of-function","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis via pharmacological perturbation and siRNA, single lab, two orthogonal methods","pmids":["22561749"],"is_preprint":false},{"year":2013,"finding":"RAB11B mediates keratinocyte-stimulated exocytosis of melanin (melanocores) from melanocytes, which is then endocytosed by keratinocytes. Depletion of RAB11B (but not RAB27A) markedly decreased both keratinocyte-stimulated melanin exocytosis and melanin transfer to keratinocytes.","method":"siRNA depletion of RAB11B vs RAB27A, electron microscopy of human skin, melanocyte-keratinocyte co-culture, functional transfer assay","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific siRNA knockdown with isoform specificity control, electron microscopy, functional transfer assay, single lab","pmids":["24141907"],"is_preprint":false},{"year":2013,"finding":"GRAB (RAB3IL1/Rabin3-like 1) is a direct binding partner of RAB11B (and RAB11A but not RAB25). The RAB11B-binding region of GRAB maps to its carboxy-terminus, distinct from its GEF domain. Exogenous expression of RAB11B shifts GRAB distribution from cytoplasm to membranes. A GRAB deletion mutant (GRABΔ223-228) is deficient in RAB11B binding.","method":"Co-immunoprecipitation, deletion mutagenesis, subcellular localization by microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus deletion mutagenesis plus localization shift, single lab","pmids":["24140058"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the cGMP-dependent protein kinase II (PKG II) leucine zipper domain in complex with RAB11B was solved. The PKG II LZ domain dimerizes and interacts with RAB11B via a mostly nonpolar surface; contact surfaces in RAB11B include switch I and II, interswitch, and β1/N-terminal regions. This binding surface differs from the Rab11-family interacting protein (Rab11-FIP) complex surfaces.","method":"X-ray crystallography, mutagenic analysis, in vitro binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis in single rigorous study","pmids":["25070890"],"is_preprint":false},{"year":2015,"finding":"RAB11B (not RAB11A) is required for recycling of PAR1 (protease-activated receptor-1). siRNA depletion of RAB11B blocks PAR1 recycling and enhances lysosomal degradation of the receptor; in RAB11B-depleted cells, enhanced PAR1 degradation is redirected through an autophagic pathway (blocked by co-depletion of RAB11A or ATG5).","method":"siRNA library screen (140 trafficking proteins), targeted siRNA knockdown of RAB11B vs RAB11A, receptor recycling/degradation assays, fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional siRNA screen followed by mechanistic validation with multiple knockdowns, single lab","pmids":["26635365"],"is_preprint":false},{"year":2017,"finding":"Two recurrent de novo missense mutations in RAB11B (p.Val22Met, p.Ala68Thr) alter the GTP/GDP binding pocket, produce localization patterns resembling inactive RAB11B, and induce RAB11B binding to the GEF SH3BP5, similar to inactive (GDP-bound) RAB11B, causing a neurodevelopmental syndrome with severe intellectual disability.","method":"3D protein structure modeling, subcellular localization studies, binary interaction assay with effectors/GEFs (including SH3BP5)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural modeling plus functional localization and interaction assays, multiple patients/mutations, single study","pmids":["29106825"],"is_preprint":false},{"year":2020,"finding":"RAB11B mediates recycling of integrin β1 to the cell surface, controlling the surface proteome during breast cancer brain metastatic adaptation. RAB11B-mediated integrin β1 surface expression enables engagement with brain ECM and activates mechanotransduction signaling for survival. Lipophilic statins prevent membrane association and activity of RAB11B.","method":"Time-course RNA-seq, Drosophila genetic screen, proteomic analysis of cell surface proteome, RAB11B loss-of-function, integrin β1 surface expression assays, statin treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (genetic screen, proteomics, functional assay, pharmacology), single lab","pmids":["32541798"],"is_preprint":false},{"year":2020,"finding":"RAB11B inhibits osteoclastogenesis by directing c-Fms and RANK surface receptors to lysosomes for proteolytic degradation via early endosome–late endosome–lysosome axis; RAB11B overexpression enlarges early and late endosomes and abolishes surface RANK/c-Fms, attenuating NFATc1 signaling. Lysosomal inhibitor chloroquine rescued receptor degradation.","method":"RAW-D and bone marrow macrophage differentiation assay, RAB11B overexpression, chloroquine inhibition, immunofluorescence, endosome size measurement","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with pharmacological rescue, multiple cell types, single lab","pmids":["33302495"],"is_preprint":false},{"year":2021,"finding":"RAB11B is an HSP90 client protein; RAB11B interacts with HSP90α and HSP90β in osteoclasts via the HSP90 ATPase domain (not requiring ATPase activity for turnover). Blocking HSP90–RAB11B interaction (by siHSP90 or 17-AAG) abrogates RAB11B-mediated lysosomal trafficking of c-Fms and RANK, thus alleviating RAB11B-dependent inhibition of osteoclastogenesis.","method":"Co-immunoprecipitation, siRNA knockdown, pharmacological inhibition (17-AAG), in vitro osteoclastogenesis","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pharmacological/siRNA rescue experiments, single lab","pmids":["34242681"],"is_preprint":false},{"year":2021,"finding":"RAB11B-AS1 lncRNA (acting as a natural SINEUP) increases endogenous RAB11B protein levels without affecting RAB11B mRNA, demonstrating post-transcriptional upregulation of RAB11B by its antisense transcript through translational enhancement.","method":"CHD8 knockdown neuronal model, RT-qPCR (mRNA levels), Western blot (protein levels), SINEUP functional assay","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method per readout, indirect (antisense RNA effect on target protein)","pmids":["34880900"],"is_preprint":false},{"year":2023,"finding":"RAB11A and RAB11B redundantly control mitotic spindle function in intestinal epithelial progenitor cells. Combined knockout of both (but not single knockouts) causes defective cell cycle entry, mitotic arrest, and apoptosis with complete lethality within 3 days. RAB11B immunoprecipitates contain mitotic spindle microtubule regulators including KIF11; RAB11 disruption impairs bipolar spindle formation.","method":"Conditional double-knockout mouse model, enteroid culture, proteomic immunoprecipitation, flow cytometry, electron microscopy of spindles","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic ablation with complete penetrance phenotype, ex vivo validation, proteomic interactome, multiple orthogonal methods in one study","pmids":["37424454"],"is_preprint":false},{"year":2025,"finding":"RAB11B is required for mitochondrial structural and functional integrity in gut epithelial cells (specifically Paneth cells). Rab11b knockout mouse intestines show altered mitochondrial protein targeting, impaired mitochondrial membrane potential, increased ROS production, and severe mitochondrial membrane defects by electron microscopy; RAB11B-specific interactome contains mitochondrial regulators.","method":"Rab11b conditional knockout mouse, transcriptomics, proteomic interactome, flow cytometry (membrane potential/ROS), electron microscopy","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with multiple orthogonal readouts, single lab, single study","pmids":["40248353"],"is_preprint":false},{"year":2024,"finding":"RAB11B promotes M1-like macrophage polarization in alcohol-associated liver disease by restraining autophagic degradation of NLRP3. RAB11B overexpression in macrophages inhibits autophagic flux, suppressing LC3B-mediated NLRP3 degradation; macrophage-specific RAB11B knockdown alleviates alcohol-induced liver inflammation.","method":"Macrophage-specific AAV knockdown, RAB11B overexpression in BMDM/RAW264.7, autophagic flux assay, immunofluorescence, in vivo ALD mouse model","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV-mediated knockdown plus in vitro mechanistic assays, single lab","pmids":["38992121"],"is_preprint":false},{"year":2025,"finding":"RAB11B (but not RAB11A) is required for H3N2 influenza A virus binding and entry; depletion of RAB11B reduced H3N2 virion binding to the cell surface by ~50%. This phenotype maps to the HA gene of H3N2 via reverse genetics and is not due to global changes in sialic acid levels but likely reflects loss of a specific sialylated surface protein(s) normally maintained at the surface by RAB11B recycling.","method":"siRNA depletion, single-cycle infection, RT-qPCR of bound virions, flow cytometry, reverse genetics/reassortant viruses, neuraminidase treatment","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (siRNA, genetic mapping, flow cytometry, virion binding assay), single lab","pmids":["42227759"],"is_preprint":false},{"year":2025,"finding":"RAB11B (but not RAB11A) controls NLRP3 inflammasome activation in human macrophages downstream of RAB11-FIP2. RAB11-FIP2 interacts with NLRP3 via its N-terminal C2-domain (NLRP3 binds via KMKK motif); RAB11-FIP2 and RAB11B regulate caspase-1-mediated cleavage of pro-IL-1β and GSDMD and pyroptotic cell death on early endosomes; PI4P-positive endosome and ASC-speck formation are also controlled by this complex.","method":"Co-immunoprecipitation (FIP2-NLRP3 domain mapping), siRNA knockdown of RAB11B vs RAB11A, caspase-1 cleavage assay, GSDMD cleavage, pyroptosis assay, PI4P endosome imaging","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP domain mapping plus functional siRNA in human macrophages with multiple readouts, single lab, preprint","pmids":["bio_10.1101_2025.05.19.654879"],"is_preprint":true}],"current_model":"RAB11B is a small Rab GTPase that functions as an isoform-specific regulator of endosomal recycling and vesicle trafficking: it controls apical recycling of ion channels/transporters (CFTR, ENaC, V-ATPase), mediates integrin β1 recycling and melanin exocytosis, promotes lysosomal degradation of surface receptors (c-Fms, RANK) in osteoclasts, redundantly controls mitotic spindle function with RAB11A, regulates NLRP3 inflammasome activation on early endosomes, and interacts structurally with PKG II leucine zipper and functionally with HSP90, GRAB, Rip11, and SH3BP5; disease-associated GTP/GDP-binding pocket mutations lock RAB11B in an inactive state causing neurodevelopmental syndrome."},"narrative":{"mechanistic_narrative":"RAB11B is a small Rab GTPase that acts as an isoform-specific regulator of endosomal recycling, controlling the surface delivery and turnover of membrane proteins from recycling endosomes through a GTP/GDP nucleotide switch [PMID:10942597, PMID:14567990]. It localizes to transferrin-positive recycling endosomes and to an apical pericentrosomal compartment that is distinct from and less microtubule-dependent than the compartment occupied by RAB11A, establishing a non-redundant identity from its closest paralog [PMID:10942597, PMID:14567990]. Through this recycling activity RAB11B selectively governs apical surface expression of ion channels and transporters—CFTR, the epithelial Na+ channel ENaC, and acidosis-induced trafficking of V-ATPase—effects not substituted by RAB11A [PMID:19244346, PMID:22129970, PMID:20717956]; the same recycling machinery drives integrin β1 return to the surface during metastatic adaptation and keratinocyte-stimulated melanin exocytosis [PMID:32541798, PMID:24141907]. RAB11B also determines receptor fate by routing cargo toward degradation: it limits Cav1.2 channel density and directs c-Fms and RANK to lysosomes via an early-to-late-endosome–lysosome axis, thereby restraining osteoclastogenesis [PMID:21248079, PMID:33302495]. Beyond recycling it has acquired roles in inflammasome control, restraining autophagic degradation of NLRP3 and, together with RAB11-FIP2, organizing NLRP3 inflammasome assembly and pyroptosis on early endosomes [PMID:38992121, PMID:bio_10.1101_2025.05.19.654879], and it redundantly cooperates with RAB11A to support mitotic spindle function, co-precipitating spindle regulators including KIF11 [PMID:37424454]. Structurally, RAB11B engages partners through its switch and interswitch surfaces, as defined by its crystal complex with the PKG II leucine zipper, and its activity depends on HSP90 chaperoning and on regulators such as GRAB and SH3BP5 [PMID:25070890, PMID:34242681, PMID:24140058, PMID:29106825]. De novo missense mutations (p.Val22Met, p.Ala68Thr) in the GTP/GDP-binding pocket lock RAB11B in an inactive, GDP-mimicking state and cause a neurodevelopmental syndrome with severe intellectual disability [PMID:29106825].","teleology":[{"year":2000,"claim":"Established RAB11B as a functional regulator of endosomal recycling rather than merely a recycling-endosome resident, by showing nucleotide cycling and membrane attachment are both required for transferrin return to the surface.","evidence":"GFP-tagged active/inactive/prenylation-deficient mutants with transferrin recycling and colocalization assays","pmids":["10942597"],"confidence":"Medium","gaps":["Effectors mediating the recycling step not identified","No distinction yet from RAB11A function"]},{"year":2003,"claim":"Defined RAB11B as a GTP-dependent switch between regulated and constitutive secretion in neuroendocrine cells and as a compartment distinct from RAB11A in polarized epithelia, beginning to separate paralog functions.","evidence":"PC12 hGH secretion assays with locked mutants; immunofluorescence and microtubule perturbation in MDCK and parietal cells","pmids":["14627637","14567990"],"confidence":"Medium","gaps":["Molecular basis of RAB11A/RAB11B compartment segregation unknown","Cargo specificity not yet mapped"]},{"year":2009,"claim":"Demonstrated isoform-specific, non-redundant control of a defined cargo (CFTR), showing RAB11B but not RAB11A drives apical CFTR recycling and surface density.","evidence":"Dominant-negative/constitutively active mutants, RNAi, halide efflux, surface biotinylation and recycling-protection assays in T84 cells","pmids":["19244346"],"confidence":"High","gaps":["Effector linking RAB11B to CFTR not identified","Generalization beyond CFTR untested at this point"]},{"year":2011,"claim":"Extended isoform-specific recycling to multiple epithelial transporters and showed RAB11B can also direct cargo to degradation, broadening its functional repertoire beyond anterograde recycling.","evidence":"Ussing chamber Na+ transport (ENaC), patch clamp and biotinylation (Cav1.2), Co-IP and siRNA for V-ATPase ε subunit with Rip11","pmids":["22129970","21248079","20717956"],"confidence":"Medium","gaps":["How RAB11B selects recycling versus degradative fate is unresolved","Direct vs effector-mediated cargo recognition unclear"]},{"year":2012,"claim":"Placed RAB11B downstream of a signaling cascade by showing cAMP/PKA/CREB transcriptionally controls RAB11B expression to drive V-ATPase trafficking, linking second-messenger signaling to recycling capacity.","evidence":"Pharmacological PKA/Src/ERK perturbation, RT-PCR, immunoblot, siRNA in salivary duct cells","pmids":["22561749"],"confidence":"Medium","gaps":["Direct CREB binding to RAB11B promoter not shown","Other transcriptional inputs unexplored"]},{"year":2013,"claim":"Identified RAB11B's direct binding partner GRAB and a physiological exocytic role in melanin transfer, beginning to define the protein interaction surface and tissue-specific outputs.","evidence":"Co-IP and deletion mapping of GRAB; siRNA depletion with electron microscopy and melanocyte–keratinocyte transfer assay","pmids":["24140058","24141907"],"confidence":"Medium","gaps":["Functional consequence of GRAB binding for recycling not established","Whether GRAB acts as GEF for RAB11B untested"]},{"year":2014,"claim":"Resolved the structural basis of a RAB11B protein interaction, mapping the PKG II leucine zipper binding to switch I/II, interswitch and β1/N-terminal surfaces distinct from Rab11-FIP contacts.","evidence":"X-ray crystallography of the PKG II LZ–RAB11B complex with mutagenesis and in vitro binding","pmids":["25070890"],"confidence":"High","gaps":["Cellular consequence of PKG II–RAB11B interaction not defined","Whether binding regulates RAB11B nucleotide state unknown"]},{"year":2015,"claim":"Showed RAB11B selectively recycles PAR1 and that its loss diverts cargo to lysosomal/autophagic degradation, establishing a recycling-versus-degradation decision node.","evidence":"siRNA trafficking screen, targeted RAB11B vs RAB11A knockdown, receptor recycling/degradation assays with ATG5 co-depletion","pmids":["26635365"],"confidence":"Medium","gaps":["Mechanism routing cargo to autophagy upon RAB11B loss unclear","Effector specificity for PAR1 not identified"]},{"year":2017,"claim":"Linked RAB11B directly to human disease, showing GTP/GDP-pocket missense mutations lock the protein in an inactive, SH3BP5-binding state and cause a neurodevelopmental syndrome.","evidence":"Structural modeling, subcellular localization, and binary interaction assays with effectors/GEFs in patients with de novo mutations","pmids":["29106825"],"confidence":"Medium","gaps":["Neuronal cargo/pathway disrupted in patients not identified","No animal model of the specific mutations"]},{"year":2020,"claim":"Connected RAB11B recycling to cancer cell adaptation and demonstrated pharmacological tractability, showing integrin β1 recycling enables mechanotransduction during brain metastasis and is blocked by statins.","evidence":"Drosophila genetic screen, surface proteomics, loss-of-function and integrin surface assays, statin treatment","pmids":["32541798"],"confidence":"Medium","gaps":["Direct RAB11B–integrin recycling machinery not defined","Specificity of statin effect for RAB11B over other prenylated proteins unclear"]},{"year":2021,"claim":"Defined how RAB11B activity is supported and amplified, identifying it as an HSP90 client required for its lysosomal trafficking function and showing a SINEUP lncRNA enhances RAB11B translation.","evidence":"Reciprocal Co-IP, siRNA and 17-AAG in osteoclasts; RT-qPCR/Western with RAB11B-AS1 SINEUP assay in neuronal model","pmids":["34242681","34880900"],"confidence":"Medium","gaps":["How HSP90 stabilizes RAB11B function mechanistically unclear","SINEUP regulation rests on a single low-confidence study"]},{"year":2023,"claim":"Revealed redundancy with RAB11A in an essential process, showing combined loss causes mitotic arrest and lethality and that RAB11B associates with spindle regulators including KIF11.","evidence":"Conditional double-knockout mouse, enteroid culture, proteomic IP, flow cytometry, spindle electron microscopy","pmids":["37424454"],"confidence":"High","gaps":["Whether spindle role is direct or via recycling membrane is unresolved","KIF11 interaction not shown to be direct"]},{"year":2024,"claim":"Established a role in inflammation, showing RAB11B restrains autophagic degradation of NLRP3 to drive M1 macrophage polarization in alcohol-associated liver disease.","evidence":"Macrophage-specific AAV knockdown, overexpression in BMDM/RAW264.7, autophagic flux assays, in vivo ALD model","pmids":["38992121"],"confidence":"Medium","gaps":["Direct molecular link between RAB11B and autophagic machinery unclear","Whether NLRP3 is a recycling cargo not addressed"]},{"year":2025,"claim":"Expanded RAB11B's roles to mitochondrial integrity, antiviral cargo maintenance, and endosomal inflammasome assembly, indicating its recycling activity shapes surface and organellar proteomes across contexts.","evidence":"Rab11b knockout mouse mitochondrial assays; siRNA and reverse genetics for H3N2 entry; FIP2–NLRP3 domain mapping with pyroptosis/PI4P endosome readouts (preprint)","pmids":["40248353","42227759","bio_10.1101_2025.05.19.654879"],"confidence":"Medium","gaps":["Mechanism linking a recycling GTPase to mitochondrial integrity unexplained","Identity of the sialylated surface protein required for H3N2 entry unknown","Inflammasome findings rest on a single preprint"]},{"year":null,"claim":"How RAB11B distinguishes recycling-to-surface from routing-to-degradation cargo, and which effectors confer its non-redundant specificity relative to RAB11A, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying effector code for cargo-fate decisions","Structural basis of RAB11A/RAB11B functional divergence undefined","Connection between membrane recycling and mitochondrial/spindle phenotypes mechanistically unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,1,3,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,19,21]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2,14,21]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,3,4]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[2,17]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3,4,11]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,6,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,21]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[17]}],"complexes":[],"partners":["RAB11FIP2","GRAB","SH3BP5","HSP90AA1","HSP90AB1","PRKG2","KIF11","ATP6V1E1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15907","full_name":"Ras-related protein Rab-11B","aliases":["GTP-binding protein YPT3"],"length_aa":218,"mass_kda":24.5,"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 (PubMed:14627637, PubMed:19029296, PubMed:19244346, PubMed:20717956, PubMed:21248079, PubMed:22129970, PubMed:26032412). RAB11B plays a role in endocytic recycling, regulating apical recycling of several transmembrane proteins including cystic fibrosis transmembrane conductance regulator/CFTR, epithelial sodium channel/ENaC, potassium voltage-gated channel, and voltage-dependent L-type calcium channel. May also regulate constitutive and regulated secretion, like insulin granule exocytosis. Required for melanosome transport and release from melanocytes. Also regulates V-ATPase intracellular transport in response to extracellular acidosis (PubMed:14627637, PubMed:19029296, PubMed:19244346, PubMed:20717956, PubMed:21248079, PubMed:22129970). Promotes Rabin8/RAB3IP preciliary vesicular trafficking to mother centriole by forming a ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, thereby regulating ciliogenesis initiation (PubMed:25673879). On the contrary, upon LPAR1 receptor signaling pathway activation, interaction with phosphorylated WDR44 prevents Rab11-RAB3IP-RAB11FIP3 complex formation and cilia growth (PubMed:31204173). Also interacts with RABL3 to promote ciliary vesicle formation (PubMed:36052645)","subcellular_location":"Recycling endosome membrane; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Cytoplasmic vesicle, phagosome membrane; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/Q15907/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB11B","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000185236","cell_line_id":"CID000417","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"RAB11A","stoichiometry":10.0},{"gene":"SCAMP2","stoichiometry":10.0},{"gene":"SCAMP4","stoichiometry":4.0},{"gene":"VAMP3","stoichiometry":4.0},{"gene":"ELOVL1","stoichiometry":0.2},{"gene":"GDI1","stoichiometry":0.2},{"gene":"GDI2","stoichiometry":0.2},{"gene":"VAMP3;VAMP2","stoichiometry":0.2},{"gene":"SLC35F2","stoichiometry":0.2},{"gene":"RAB11FIP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000417","total_profiled":1310},"omim":[{"mim_id":"621025","title":"RAB3A-INTERACTING PROTEIN-LIKE 1; RAB3IL1","url":"https://www.omim.org/entry/621025"},{"mim_id":"618001","title":"RAB11 EFFECTOR CONTAINING LIS1 HOMOLOGY DOMAIN, COILED-COIL DOMAINS, AND HEAT REPEATS; RELCH","url":"https://www.omim.org/entry/618001"},{"mim_id":"617807","title":"NEURODEVELOPMENTAL DISORDER WITH ATAXIC GAIT, ABSENT SPEECH, AND DECREASED CORTICAL WHITE MATTER; NDAGSCW","url":"https://www.omim.org/entry/617807"},{"mim_id":"614855","title":"TBC1 DOMAIN FAMILY, MEMBER 14; TBC1D14","url":"https://www.omim.org/entry/614855"},{"mim_id":"608738","title":"RAB11 FAMILY-INTERACTING PROTEIN 3; RAB11FIP3","url":"https://www.omim.org/entry/608738"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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\"RAB11B localizes to transferrin-positive recycling endosomes and is essential for recycling of internalized transferrin to the plasma membrane. Constitutively active (Q/L) and constitutively inactive (S/N) mutants both blocked transferrin recycling without affecting uptake; a prenylation-deficient mutant (ΔC) had no effect, indicating membrane association is required.\",\n      \"method\": \"GFP-tagged mutant overexpression, transferrin recycling assay, subcellular colocalization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean functional assay with multiple mutants in single lab, two orthogonal methods (colocalization + recycling assay)\",\n      \"pmids\": [\"10942597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RAB11B in PC12 cells colocalizes with secretory vesicle markers. GDP-bound RAB11B stimulates constitutive secretion and depletes vesicular stores, while GTP-bound RAB11B directly impairs Ca2+-triggered exocytosis, demonstrating a GTP-dependent switch between regulated and constitutive secretory pathways in neuronal/neuroendocrine cells.\",\n      \"method\": \"Transfected hGH reporter in PC12 cells, constitutively active/inactive RAB11B mutants, secretion assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional exocytosis assay with GTP/GDP-locked mutants, single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"14627637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Endogenous RAB11B localizes to an apical pericentrisomal compartment distinct from RAB11A in polarized epithelial cells (MDCK and gastric parietal cells); its distribution is less dependent on microtubules than RAB11A, and it does not substantially colocalize with transferrin or IgA cargo handled by RAB11A.\",\n      \"method\": \"Immunofluorescence of endogenous proteins, nocodazole/taxol perturbation, subcellular fractionation/coisolation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional microtubule perturbation, single lab, multiple cell types\",\n      \"pmids\": [\"14567990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RAB11B (but not RAB11A) selectively regulates apical recycling of CFTR in polarized intestinal epithelial (T84) cells. GDP-locked RAB11B-S25N inhibited ~80% of cAMP-activated halide efflux and reduced apical membrane CFTR by 50%; constitutively active RAB11B-Q70L increased stimulated efflux; RNAi knockdown of RAB11B (not RAB11A) reduced anion conductance by 50%.\",\n      \"method\": \"Dominant-negative/constitutively active mutant expression, RNAi knockdown, halide efflux assay, cell surface biotinylation, biotin protection recycling assay, immunoisolation of vesicles\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (dominant negative, constitutively active, RNAi, biotinylation, recycling protection assay) converging on same conclusion in single rigorous study\",\n      \"pmids\": [\"19244346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RAB11B regulates apical recycling and surface expression of the epithelial sodium channel ENaC. Dominant-negative RAB11B (but not RAB11A) most effectively reduced basal and cAMP-stimulated ENaC-dependent Na+ transport; siRNA knockdown of RAB11B demonstrated its requirement for ENaC surface expression in mpkCCD cells.\",\n      \"method\": \"Dominant-negative mutant expression, siRNA knockdown, Ussing chamber Na+ transport assay, immunoisolation, confocal colocalization\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ion transport assays plus siRNA, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22129970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RAB11B (not RAB11A) limits plasma membrane density of Cav1.2 L-type Ca2+ channels by promoting their degradation. Dominant-negative RAB11B-S25N or shRNA knockdown of RAB11B increased peak L-type Ba2+ current by ~64–66% and increased surface Cav1.2 density; cell surface biotinylation showed the effect is on degradation, not anterograde trafficking.\",\n      \"method\": \"Dominant-negative mutant, shRNA knockdown, whole-cell patch clamp, cell surface biotinylation, HA-tagged channel\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (dominant negative, shRNA, electrophysiology, biotinylation) in single lab\",\n      \"pmids\": [\"21248079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RAB11B and its effector Rip11 regulate acidosis-induced trafficking of V-ATPase to the plasma membrane in salivary duct cells. RAB11B showed higher colocalization with V-ATPase than RAB11A; RAB11 (not RAB25) interacts with the ε subunit of V-ATPase; siRNA knockdown of RAB11B or Rip11 prevented acidosis-induced V-ATPase translocation.\",\n      \"method\": \"siRNA knockdown, confocal colocalization, co-immunoprecipitation (RAB11/V-ATPase ε subunit), immunofluorescence\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional siRNA knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"20717956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The cAMP/PKA/CREB signaling pathway controls acidosis-induced V-ATPase trafficking in salivary ducts via transcriptional regulation of RAB11B expression; PKA phosphorylates CREB which activates RAB11B transcription, and CREB loss-of-function downregulates RAB11B and impairs V-ATPase translocation.\",\n      \"method\": \"Pharmacological inhibitors/activators of PKA/Src/ERK, RT-PCR, immunoblotting, siRNA loss-of-function\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis via pharmacological perturbation and siRNA, single lab, two orthogonal methods\",\n      \"pmids\": [\"22561749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAB11B mediates keratinocyte-stimulated exocytosis of melanin (melanocores) from melanocytes, which is then endocytosed by keratinocytes. Depletion of RAB11B (but not RAB27A) markedly decreased both keratinocyte-stimulated melanin exocytosis and melanin transfer to keratinocytes.\",\n      \"method\": \"siRNA depletion of RAB11B vs RAB27A, electron microscopy of human skin, melanocyte-keratinocyte co-culture, functional transfer assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific siRNA knockdown with isoform specificity control, electron microscopy, functional transfer assay, single lab\",\n      \"pmids\": [\"24141907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GRAB (RAB3IL1/Rabin3-like 1) is a direct binding partner of RAB11B (and RAB11A but not RAB25). The RAB11B-binding region of GRAB maps to its carboxy-terminus, distinct from its GEF domain. Exogenous expression of RAB11B shifts GRAB distribution from cytoplasm to membranes. A GRAB deletion mutant (GRABΔ223-228) is deficient in RAB11B binding.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutagenesis, subcellular localization by microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus deletion mutagenesis plus localization shift, single lab\",\n      \"pmids\": [\"24140058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the cGMP-dependent protein kinase II (PKG II) leucine zipper domain in complex with RAB11B was solved. The PKG II LZ domain dimerizes and interacts with RAB11B via a mostly nonpolar surface; contact surfaces in RAB11B include switch I and II, interswitch, and β1/N-terminal regions. This binding surface differs from the Rab11-family interacting protein (Rab11-FIP) complex surfaces.\",\n      \"method\": \"X-ray crystallography, mutagenic analysis, in vitro binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis in single rigorous study\",\n      \"pmids\": [\"25070890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RAB11B (not RAB11A) is required for recycling of PAR1 (protease-activated receptor-1). siRNA depletion of RAB11B blocks PAR1 recycling and enhances lysosomal degradation of the receptor; in RAB11B-depleted cells, enhanced PAR1 degradation is redirected through an autophagic pathway (blocked by co-depletion of RAB11A or ATG5).\",\n      \"method\": \"siRNA library screen (140 trafficking proteins), targeted siRNA knockdown of RAB11B vs RAB11A, receptor recycling/degradation assays, fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional siRNA screen followed by mechanistic validation with multiple knockdowns, single lab\",\n      \"pmids\": [\"26635365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Two recurrent de novo missense mutations in RAB11B (p.Val22Met, p.Ala68Thr) alter the GTP/GDP binding pocket, produce localization patterns resembling inactive RAB11B, and induce RAB11B binding to the GEF SH3BP5, similar to inactive (GDP-bound) RAB11B, causing a neurodevelopmental syndrome with severe intellectual disability.\",\n      \"method\": \"3D protein structure modeling, subcellular localization studies, binary interaction assay with effectors/GEFs (including SH3BP5)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural modeling plus functional localization and interaction assays, multiple patients/mutations, single study\",\n      \"pmids\": [\"29106825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB11B mediates recycling of integrin β1 to the cell surface, controlling the surface proteome during breast cancer brain metastatic adaptation. RAB11B-mediated integrin β1 surface expression enables engagement with brain ECM and activates mechanotransduction signaling for survival. Lipophilic statins prevent membrane association and activity of RAB11B.\",\n      \"method\": \"Time-course RNA-seq, Drosophila genetic screen, proteomic analysis of cell surface proteome, RAB11B loss-of-function, integrin β1 surface expression assays, statin treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (genetic screen, proteomics, functional assay, pharmacology), single lab\",\n      \"pmids\": [\"32541798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAB11B inhibits osteoclastogenesis by directing c-Fms and RANK surface receptors to lysosomes for proteolytic degradation via early endosome–late endosome–lysosome axis; RAB11B overexpression enlarges early and late endosomes and abolishes surface RANK/c-Fms, attenuating NFATc1 signaling. Lysosomal inhibitor chloroquine rescued receptor degradation.\",\n      \"method\": \"RAW-D and bone marrow macrophage differentiation assay, RAB11B overexpression, chloroquine inhibition, immunofluorescence, endosome size measurement\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with pharmacological rescue, multiple cell types, single lab\",\n      \"pmids\": [\"33302495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB11B is an HSP90 client protein; RAB11B interacts with HSP90α and HSP90β in osteoclasts via the HSP90 ATPase domain (not requiring ATPase activity for turnover). Blocking HSP90–RAB11B interaction (by siHSP90 or 17-AAG) abrogates RAB11B-mediated lysosomal trafficking of c-Fms and RANK, thus alleviating RAB11B-dependent inhibition of osteoclastogenesis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, pharmacological inhibition (17-AAG), in vitro osteoclastogenesis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pharmacological/siRNA rescue experiments, single lab\",\n      \"pmids\": [\"34242681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB11B-AS1 lncRNA (acting as a natural SINEUP) increases endogenous RAB11B protein levels without affecting RAB11B mRNA, demonstrating post-transcriptional upregulation of RAB11B by its antisense transcript through translational enhancement.\",\n      \"method\": \"CHD8 knockdown neuronal model, RT-qPCR (mRNA levels), Western blot (protein levels), SINEUP functional assay\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method per readout, indirect (antisense RNA effect on target protein)\",\n      \"pmids\": [\"34880900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAB11A and RAB11B redundantly control mitotic spindle function in intestinal epithelial progenitor cells. Combined knockout of both (but not single knockouts) causes defective cell cycle entry, mitotic arrest, and apoptosis with complete lethality within 3 days. RAB11B immunoprecipitates contain mitotic spindle microtubule regulators including KIF11; RAB11 disruption impairs bipolar spindle formation.\",\n      \"method\": \"Conditional double-knockout mouse model, enteroid culture, proteomic immunoprecipitation, flow cytometry, electron microscopy of spindles\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic ablation with complete penetrance phenotype, ex vivo validation, proteomic interactome, multiple orthogonal methods in one study\",\n      \"pmids\": [\"37424454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAB11B is required for mitochondrial structural and functional integrity in gut epithelial cells (specifically Paneth cells). Rab11b knockout mouse intestines show altered mitochondrial protein targeting, impaired mitochondrial membrane potential, increased ROS production, and severe mitochondrial membrane defects by electron microscopy; RAB11B-specific interactome contains mitochondrial regulators.\",\n      \"method\": \"Rab11b conditional knockout mouse, transcriptomics, proteomic interactome, flow cytometry (membrane potential/ROS), electron microscopy\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with multiple orthogonal readouts, single lab, single study\",\n      \"pmids\": [\"40248353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAB11B promotes M1-like macrophage polarization in alcohol-associated liver disease by restraining autophagic degradation of NLRP3. RAB11B overexpression in macrophages inhibits autophagic flux, suppressing LC3B-mediated NLRP3 degradation; macrophage-specific RAB11B knockdown alleviates alcohol-induced liver inflammation.\",\n      \"method\": \"Macrophage-specific AAV knockdown, RAB11B overexpression in BMDM/RAW264.7, autophagic flux assay, immunofluorescence, in vivo ALD mouse model\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV-mediated knockdown plus in vitro mechanistic assays, single lab\",\n      \"pmids\": [\"38992121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAB11B (but not RAB11A) is required for H3N2 influenza A virus binding and entry; depletion of RAB11B reduced H3N2 virion binding to the cell surface by ~50%. This phenotype maps to the HA gene of H3N2 via reverse genetics and is not due to global changes in sialic acid levels but likely reflects loss of a specific sialylated surface protein(s) normally maintained at the surface by RAB11B recycling.\",\n      \"method\": \"siRNA depletion, single-cycle infection, RT-qPCR of bound virions, flow cytometry, reverse genetics/reassortant viruses, neuraminidase treatment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (siRNA, genetic mapping, flow cytometry, virion binding assay), single lab\",\n      \"pmids\": [\"42227759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAB11B (but not RAB11A) controls NLRP3 inflammasome activation in human macrophages downstream of RAB11-FIP2. RAB11-FIP2 interacts with NLRP3 via its N-terminal C2-domain (NLRP3 binds via KMKK motif); RAB11-FIP2 and RAB11B regulate caspase-1-mediated cleavage of pro-IL-1β and GSDMD and pyroptotic cell death on early endosomes; PI4P-positive endosome and ASC-speck formation are also controlled by this complex.\",\n      \"method\": \"Co-immunoprecipitation (FIP2-NLRP3 domain mapping), siRNA knockdown of RAB11B vs RAB11A, caspase-1 cleavage assay, GSDMD cleavage, pyroptosis assay, PI4P endosome imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP domain mapping plus functional siRNA in human macrophages with multiple readouts, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.05.19.654879\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RAB11B is a small Rab GTPase that functions as an isoform-specific regulator of endosomal recycling and vesicle trafficking: it controls apical recycling of ion channels/transporters (CFTR, ENaC, V-ATPase), mediates integrin β1 recycling and melanin exocytosis, promotes lysosomal degradation of surface receptors (c-Fms, RANK) in osteoclasts, redundantly controls mitotic spindle function with RAB11A, regulates NLRP3 inflammasome activation on early endosomes, and interacts structurally with PKG II leucine zipper and functionally with HSP90, GRAB, Rip11, and SH3BP5; disease-associated GTP/GDP-binding pocket mutations lock RAB11B in an inactive state causing neurodevelopmental syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB11B is a small Rab GTPase that acts as an isoform-specific regulator of endosomal recycling, controlling the surface delivery and turnover of membrane proteins from recycling endosomes through a GTP/GDP nucleotide switch [#0, #2]. It localizes to transferrin-positive recycling endosomes and to an apical pericentrosomal compartment that is distinct from and less microtubule-dependent than the compartment occupied by RAB11A, establishing a non-redundant identity from its closest paralog [#0, #2]. Through this recycling activity RAB11B selectively governs apical surface expression of ion channels and transporters\\u2014CFTR, the epithelial Na+ channel ENaC, and acidosis-induced trafficking of V-ATPase\\u2014effects not substituted by RAB11A [#3, #4, #6]; the same recycling machinery drives integrin \\u03b21 return to the surface during metastatic adaptation and keratinocyte-stimulated melanin exocytosis [#13, #8]. RAB11B also determines receptor fate by routing cargo toward degradation: it limits Cav1.2 channel density and directs c-Fms and RANK to lysosomes via an early-to-late-endosome\\u2013lysosome axis, thereby restraining osteoclastogenesis [#5, #14]. Beyond recycling it has acquired roles in inflammasome control, restraining autophagic degradation of NLRP3 and, together with RAB11-FIP2, organizing NLRP3 inflammasome assembly and pyroptosis on early endosomes [#19, #21], and it redundantly cooperates with RAB11A to support mitotic spindle function, co-precipitating spindle regulators including KIF11 [#17]. Structurally, RAB11B engages partners through its switch and interswitch surfaces, as defined by its crystal complex with the PKG II leucine zipper, and its activity depends on HSP90 chaperoning and on regulators such as GRAB and SH3BP5 [#10, #15, #9, #12]. De novo missense mutations (p.Val22Met, p.Ala68Thr) in the GTP/GDP-binding pocket lock RAB11B in an inactive, GDP-mimicking state and cause a neurodevelopmental syndrome with severe intellectual disability [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established RAB11B as a functional regulator of endosomal recycling rather than merely a recycling-endosome resident, by showing nucleotide cycling and membrane attachment are both required for transferrin return to the surface.\",\n      \"evidence\": \"GFP-tagged active/inactive/prenylation-deficient mutants with transferrin recycling and colocalization assays\",\n      \"pmids\": [\"10942597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effectors mediating the recycling step not identified\", \"No distinction yet from RAB11A function\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined RAB11B as a GTP-dependent switch between regulated and constitutive secretion in neuroendocrine cells and as a compartment distinct from RAB11A in polarized epithelia, beginning to separate paralog functions.\",\n      \"evidence\": \"PC12 hGH secretion assays with locked mutants; immunofluorescence and microtubule perturbation in MDCK and parietal cells\",\n      \"pmids\": [\"14627637\", \"14567990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of RAB11A/RAB11B compartment segregation unknown\", \"Cargo specificity not yet mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated isoform-specific, non-redundant control of a defined cargo (CFTR), showing RAB11B but not RAB11A drives apical CFTR recycling and surface density.\",\n      \"evidence\": \"Dominant-negative/constitutively active mutants, RNAi, halide efflux, surface biotinylation and recycling-protection assays in T84 cells\",\n      \"pmids\": [\"19244346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector linking RAB11B to CFTR not identified\", \"Generalization beyond CFTR untested at this point\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended isoform-specific recycling to multiple epithelial transporters and showed RAB11B can also direct cargo to degradation, broadening its functional repertoire beyond anterograde recycling.\",\n      \"evidence\": \"Ussing chamber Na+ transport (ENaC), patch clamp and biotinylation (Cav1.2), Co-IP and siRNA for V-ATPase \\u03b5 subunit with Rip11\",\n      \"pmids\": [\"22129970\", \"21248079\", \"20717956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How RAB11B selects recycling versus degradative fate is unresolved\", \"Direct vs effector-mediated cargo recognition unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed RAB11B downstream of a signaling cascade by showing cAMP/PKA/CREB transcriptionally controls RAB11B expression to drive V-ATPase trafficking, linking second-messenger signaling to recycling capacity.\",\n      \"evidence\": \"Pharmacological PKA/Src/ERK perturbation, RT-PCR, immunoblot, siRNA in salivary duct cells\",\n      \"pmids\": [\"22561749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CREB binding to RAB11B promoter not shown\", \"Other transcriptional inputs unexplored\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified RAB11B's direct binding partner GRAB and a physiological exocytic role in melanin transfer, beginning to define the protein interaction surface and tissue-specific outputs.\",\n      \"evidence\": \"Co-IP and deletion mapping of GRAB; siRNA depletion with electron microscopy and melanocyte\\u2013keratinocyte transfer assay\",\n      \"pmids\": [\"24140058\", \"24141907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of GRAB binding for recycling not established\", \"Whether GRAB acts as GEF for RAB11B untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the structural basis of a RAB11B protein interaction, mapping the PKG II leucine zipper binding to switch I/II, interswitch and \\u03b21/N-terminal surfaces distinct from Rab11-FIP contacts.\",\n      \"evidence\": \"X-ray crystallography of the PKG II LZ\\u2013RAB11B complex with mutagenesis and in vitro binding\",\n      \"pmids\": [\"25070890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of PKG II\\u2013RAB11B interaction not defined\", \"Whether binding regulates RAB11B nucleotide state unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed RAB11B selectively recycles PAR1 and that its loss diverts cargo to lysosomal/autophagic degradation, establishing a recycling-versus-degradation decision node.\",\n      \"evidence\": \"siRNA trafficking screen, targeted RAB11B vs RAB11A knockdown, receptor recycling/degradation assays with ATG5 co-depletion\",\n      \"pmids\": [\"26635365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism routing cargo to autophagy upon RAB11B loss unclear\", \"Effector specificity for PAR1 not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked RAB11B directly to human disease, showing GTP/GDP-pocket missense mutations lock the protein in an inactive, SH3BP5-binding state and cause a neurodevelopmental syndrome.\",\n      \"evidence\": \"Structural modeling, subcellular localization, and binary interaction assays with effectors/GEFs in patients with de novo mutations\",\n      \"pmids\": [\"29106825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal cargo/pathway disrupted in patients not identified\", \"No animal model of the specific mutations\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected RAB11B recycling to cancer cell adaptation and demonstrated pharmacological tractability, showing integrin \\u03b21 recycling enables mechanotransduction during brain metastasis and is blocked by statins.\",\n      \"evidence\": \"Drosophila genetic screen, surface proteomics, loss-of-function and integrin surface assays, statin treatment\",\n      \"pmids\": [\"32541798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RAB11B\\u2013integrin recycling machinery not defined\", \"Specificity of statin effect for RAB11B over other prenylated proteins unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined how RAB11B activity is supported and amplified, identifying it as an HSP90 client required for its lysosomal trafficking function and showing a SINEUP lncRNA enhances RAB11B translation.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA and 17-AAG in osteoclasts; RT-qPCR/Western with RAB11B-AS1 SINEUP assay in neuronal model\",\n      \"pmids\": [\"34242681\", \"34880900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HSP90 stabilizes RAB11B function mechanistically unclear\", \"SINEUP regulation rests on a single low-confidence study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed redundancy with RAB11A in an essential process, showing combined loss causes mitotic arrest and lethality and that RAB11B associates with spindle regulators including KIF11.\",\n      \"evidence\": \"Conditional double-knockout mouse, enteroid culture, proteomic IP, flow cytometry, spindle electron microscopy\",\n      \"pmids\": [\"37424454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether spindle role is direct or via recycling membrane is unresolved\", \"KIF11 interaction not shown to be direct\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a role in inflammation, showing RAB11B restrains autophagic degradation of NLRP3 to drive M1 macrophage polarization in alcohol-associated liver disease.\",\n      \"evidence\": \"Macrophage-specific AAV knockdown, overexpression in BMDM/RAW264.7, autophagic flux assays, in vivo ALD model\",\n      \"pmids\": [\"38992121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between RAB11B and autophagic machinery unclear\", \"Whether NLRP3 is a recycling cargo not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded RAB11B's roles to mitochondrial integrity, antiviral cargo maintenance, and endosomal inflammasome assembly, indicating its recycling activity shapes surface and organellar proteomes across contexts.\",\n      \"evidence\": \"Rab11b knockout mouse mitochondrial assays; siRNA and reverse genetics for H3N2 entry; FIP2\\u2013NLRP3 domain mapping with pyroptosis/PI4P endosome readouts (preprint)\",\n      \"pmids\": [\"40248353\", \"42227759\", \"bio_10.1101_2025.05.19.654879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking a recycling GTPase to mitochondrial integrity unexplained\", \"Identity of the sialylated surface protein required for H3N2 entry unknown\", \"Inflammasome findings rest on a single preprint\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RAB11B distinguishes recycling-to-surface from routing-to-degradation cargo, and which effectors confer its non-redundant specificity relative to RAB11A, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying effector code for cargo-fate decisions\", \"Structural basis of RAB11A/RAB11B functional divergence undefined\", \"Connection between membrane recycling and mitochondrial/spindle phenotypes mechanistically unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1, 3, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 19, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2, 14, 21]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [2, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3, 4, 11]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 6, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 21]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB11FIP2\", \"GRAB\", \"SH3BP5\", \"HSP90AA1\", \"HSP90AB1\", \"PRKG2\", \"KIF11\", \"ATP6V1E1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}