RAB8B

RAB8B is a small Rab GTPase that functions redundantly with RAB8A to direct apical membrane trafficking and, together with RAB10, supports ciliogenesis (PMID:24213529). It promotes caveolin-dependent endocytosis of LRP6 to sustain Wnt/β-catenin signalling (PMID:24035388), mediates recycling-endosome-to-plasma-membrane transport exploited by West Nile virus and SARS-CoV-2 (PMID:26817838, PMID:42015392), and participates in regulated secretion through a guanine-nucleotide-dependent interaction with the TPR-domain protein TRIP8b (PMID:11278749). RAB8B expression in hepatocytes is post-transcriptionally suppressed by LXRα-induced miR-34a and let-7a, and its depletion impairs autophagosome–lysosome formation and lipophagy, contributing to hepatic steatosis (PMID:32557804).

1. 2001 High

   Identification of a guanine-nucleotide-dependent RAB8B–TRIP8b interaction established RAB8B as a participant in regulated secretion, answering whether this GTPase has effectors beyond constitutive traffic.

   Evidence Yeast two-hybrid, in vitro binding, co-IP, and ACTH secretion assays in AtT20 cells

   PMID:11278749

   Open questions at the time

   • Structural basis of TRIP8b TPR–RAB8B recognition not resolved at atomic level
   • Whether TRIP8b interaction is required for secretion in non-pituitary cell types unknown
   • Downstream effectors linking RAB8B–TRIP8b to vesicle fusion machinery not identified
2. 2003 Medium

   Localization of RAB8B to adherens junctions and cytoskeletal networks in the testis suggested a role in junction dynamics, extending RAB8B function beyond classical secretory trafficking.

   Evidence Immunohistochemistry, cytoskeletal co-sedimentation, and Sertoli–germ cell co-cultures

   PMID:12639940

   Open questions at the time

   • No loss-of-function experiment performed to confirm a causal role in junction assembly
   • Mechanism linking RAB8B to cytoskeletal association not defined
   • Relevance to adherens junction dynamics in other epithelia untested
3. 2008 Medium

   Discovery of a physical RAB8B–otoferlin interaction at the trans-Golgi network in cochlear tissue connected RAB8B to auditory hair-cell vesicle trafficking and the DFNB9 deafness pathway, while biochemical dissection of the TRIP8b TPR domain clarified nucleotide-dependent binding specificity.

   Evidence Yeast two-hybrid, co-IP of native cochlear proteins, co-localization in HEK293 (otoferlin); in vitro mutagenesis and binding assays (TRIP8b TPR)

   PMID:18346465 PMID:18772196

   Open questions at the time

   • No functional rescue to demonstrate that RAB8B–otoferlin interaction is required for synaptic vesicle exocytosis
   • Whether RAB8B loss phenocopies hearing defects in vivo not tested
   • Crystal structure of RAB8B–TRIP8b complex unavailable
4. 2013 High

   Genetic knockout studies resolved the long-standing question of RAB8A/RAB8B redundancy, demonstrating that both isoforms are collectively essential for apical—but not basolateral—trafficking, and revealed an additional redundancy with RAB10 in ciliogenesis.

   Evidence Rab8a/Rab8b single- and double-knockout mice with immunofluorescence; additional Rab10 siRNA in DKO cells

   PMID:24213529

   Open questions at the time

   • Molecular cargo or adaptor distinguishing apical from basolateral sorting by RAB8 isoforms not identified
   • Tissue-specific phenotypes of double KO beyond intestinal epithelia and kidney not fully catalogued
   • Mechanism by which RAB10 compensates for RAB8 loss in ciliogenesis unknown
5. 2013 High

   Demonstrating that RAB8B promotes caveolin-dependent LRP6 endocytosis connected it to Wnt/β-catenin signal transduction, showing RAB8B can regulate signalling pathway output through receptor trafficking.

   Evidence RNAi screen, knockdown/overexpression, LRP6 phosphorylation and β-catenin assays, Xenopus and zebrafish morphants

   PMID:24035388

   Open questions at the time

   • Whether RAB8B acts directly on caveolae or indirectly through recycling endosome intermediates unclear
   • Identity of RAB8B effectors mediating LRP6 internalization not determined
   • Relevance to non-canonical Wnt pathways not addressed
6. 2016 Medium

   Showing that RAB8B is required for recycling-endosome-to-plasma-membrane transport of West Nile virus particles defined the specific intracellular trafficking step controlled by RAB8B that is co-opted by viral egress.

   Evidence siRNA knockdown with quantification of WNV release and immunofluorescence co-localization in neuroblastoma cells

   PMID:26817838

   Open questions at the time

   • Whether RAB8B acts via VAMP-3 or other SNAREs in WNV egress not determined
   • Contribution of RAB8A redundancy not fully controlled
   • Applicability to other flaviviruses not tested
7. 2021 High

   Identification of LXRα–miR-34a/let-7a as a transcriptional–post-transcriptional axis that suppresses RAB8B revealed how metabolic signalling regulates autophagy and lipophagy through RAB8B abundance in hepatocytes.

   Evidence LXRα KO mouse, ChIP, 3′ UTR luciferase reporter, autophagy flux and mitochondrial respiration assays

   PMID:32557804

   Open questions at the time

   • Direct autophagosome/lysosome fusion step requiring RAB8B not molecularly defined
   • Whether RAB8B overexpression alone rescues steatosis in vivo not shown
   • Other Rab GTPases potentially co-regulated by the same miRNAs not characterized
8. 2026 Medium

   Extending the viral-hijacking paradigm to SARS-CoV-2 showed that RAB8B modulates VAMP-3 clustering and intracellular trafficking during coronavirus infection, establishing RAB8B as a broadly exploited host factor.

   Evidence siRNA silencing in SARS-CoV-2-infected CaCo-2 cells with viral infection quantification and molecular dynamics simulations

   PMID:42015392

   Open questions at the time

   • Direct RAB8B–VAMP-3 physical interaction not confirmed by co-IP or pull-down
   • Relative contribution of RAB8A versus RAB8B in coronavirus trafficking not delineated
   • Mechanism by which SARS-CoV-2 specifically engages RAB8B not identified

• Key unresolved questions include the identity of RAB8B-specific effectors and GEFs that distinguish it from RAB8A, the structural basis of its interaction with TRIP8b and otoferlin, and whether RAB8B loss causes developmental or auditory phenotypes in vivo.
• No RAB8B-specific GEF or GAP identified
• Atomic-resolution structure of RAB8B with any effector unavailable
• In vivo auditory phenotype of RAB8B single knockout not reported