RAB11FIP5

RAB11FIP5 (also called Rip11) is a Rab11 effector protein that orchestrates membrane trafficking through recycling endosomes, controlling apical transcytosis, slow endocytic recycling, regulated exocytosis, and cargo-specific integrin and receptor recycling in diverse cell types. It is recruited to subapical recycling endosomes via direct Rab11 binding and a C2 domain that interacts with neutral phospholipids in a Mg²⁺-dependent manner, and it forms functional complexes with kinesin II to direct cargo into the slow recycling pathway and with AS160 to regulate insulin-stimulated GLUT4 trafficking (PMID:11163216, PMID:18957512, PMID:18003705). RAB11FIP5 activity is regulated by phosphorylation — ERK phosphorylation controls pIgR/pIgA transcytosis downstream of a Yes–EGFR–ERK cascade, PKA phosphorylation regulates cAMP-potentiated insulin secretion in pancreatic β-cells, and TRIM21-mediated K6-linked polyubiquitination activates its transcytotic function (PMID:21037565, PMID:19335615, PMID:34638806). In neurons, RAB11FIP5 is specifically required for NMDA receptor–dependent long-term depression but dispensable for long-term potentiation, and during development it mediates ephrinB1 recycling essential for telencephalon growth (PMID:25972173, PMID:33462110).

1. 2000 High

   Identification of RAB11FIP5 as a Rab11-binding effector at the apical recycling endosome established the molecular basis by which it is recruited to membranes and participates in polarized vesicle targeting.

   Evidence Co-immunoprecipitation, lipid-binding assays, transport assays, and EM/fluorescence microscopy in polarized epithelial cells

   PMID:11163216

   Open questions at the time

   • Specific cargo sorted by RAB11FIP5 was not identified
   • Identity of the kinase(s) regulating its phosphorylation-dependent membrane association was unknown
   • Whether RAB11FIP5 functions in non-epithelial contexts was untested
2. 2003 Low

   Discovery of the γ-SNAP interaction and an alternatively spliced variant suggested RAB11FIP5 may link SNARE fusion machinery to recycling endosomes, though the functional significance remained unclear.

   Evidence Co-immunoprecipitation and overexpression with morphological analysis of recycling endosomes

   PMID:12684040

   Open questions at the time

   • Single Co-IP without reciprocal validation or functional reconstitution of γ-SNAP–dependent fusion
   • Role of the splice variant versus full-length protein in trafficking was not dissected
3. 2007 High

   Demonstration that RAB11FIP5 complexes with the RabGAP AS160 and is required for insulin-stimulated GLUT4 translocation placed it as a key node linking Rab11 recycling to metabolic signaling.

   Evidence Co-immunoprecipitation, siRNA knockdown, 2-deoxyglucose uptake, and subcellular fractionation in adipocytes

   PMID:18003705

   Open questions at the time

   • Mechanism by which insulin dissociates the AS160–RAB11FIP5 complex was unresolved
   • Whether RAB11FIP5 directly contacts GLUT4 vesicles was not shown
4. 2008 High

   Identification of kinesin II as a RAB11FIP5-binding partner that co-directs cargo into a slow recycling pathway defined the motor coupling mechanism for perinuclear endosome trafficking.

   Evidence Reciprocal Co-IP, siRNA knockdown, and receptor recycling assays with fluorescence/EM microscopy

   PMID:18957512

   Open questions at the time

   • Whether RAB11FIP5 binds kinesin II directly or via an adaptor was not fully resolved
   • Cargo selectivity of this slow recycling route was not established
5. 2009 Medium

   Showing that PKA phosphorylates RAB11FIP5 in β-cells and that a dominant-negative mutant blocks cAMP-potentiated but not basal insulin secretion established RAB11FIP5 as a regulated exocytic effector in neuroendocrine cells.

   Evidence In vivo PKA phosphorylation assay, dominant-negative mutant expression, and insulin secretion measurements in MIN6 cells

   PMID:19335615

   Open questions at the time

   • Phosphorylation site(s) on RAB11FIP5 mediating the secretory effect were not mapped
   • Whether RAB11FIP5 directly regulates granule docking or fusion was not determined
6. 2010 High

   Placing RAB11FIP5 as an ERK substrate downstream of the Yes–EGFR–ERK cascade revealed the first signal transduction pathway controlling pIgR/pIgA transcytosis through this effector.

   Evidence In vitro kinase assay, phospho-mass spectrometry, siRNA knockdown, and in vivo pIgA injection in rats

   PMID:21037565

   Open questions at the time

   • How ERK-mediated phosphorylation alters RAB11FIP5 activity or binding partners was mechanistically unresolved
   • Whether ERK phosphorylation regulates other RAB11FIP5-dependent routes beyond transcytosis was untested
7. 2011 Medium

   Demonstrating that RAB11FIP5 is required for acidosis-induced V-ATPase translocation extended its role to stimulus-responsive transporter trafficking in salivary duct cells.

   Evidence siRNA knockdown, immunofluorescence, co-immunoprecipitation, and subcellular fractionation

   PMID:20717956

   Open questions at the time

   • The signal linking acidosis to RAB11FIP5 activation was not identified
   • Whether Rab11a or Rab11b preferentially partners with RAB11FIP5 in this context was not settled
8. 2015 High

   Genetic knockout revealed that RAB11FIP5 is specifically required for hippocampal long-term depression but dispensable for LTP, uncovering a selective role in activity-dependent AMPAR removal at synapses.

   Evidence Conditional knockout mice, shRNA knockdown, electrophysiology in acute slices and cultured neurons, behavioral assays

   PMID:25972173

   Open questions at the time

   • The AMPAR subtype or trafficking step controlled by RAB11FIP5 during LTD was not defined
   • Whether RAB11FIP5 functions at pre- or postsynaptic compartments for LTD was not resolved
9. 2015 Medium

   Live-cell imaging showed that insulin increases RAB11FIP5 plasma membrane accumulation by inhibiting its dynamin- and PI3K-dependent endocytic retrieval rather than by accelerating its delivery, refining the trafficking model for its insulin-responsive behavior.

   Evidence Live-cell fluorescence microscopy with pharmacological inhibition of dynamin and PI3K

   PMID:26515129

   Open questions at the time

   • The upstream insulin signaling intermediate that inhibits RAB11FIP5 internalization was not identified
   • Relevance of this mechanism to GLUT4 vesicle insertion was not directly tested
10. 2018 Medium

    Selective regulation of α6β1 integrin but not α3β1 recycling by RAB11FIP5 demonstrated cargo specificity among Rab11 effectors and linked RAB11FIP5 to laminin-dependent cell migration.

    Evidence siRNA knockdown, flow cytometry, fluorescence microscopy, cell migration assay, and PDX tumor mouse model

    PMID:29759989

    Open questions at the time

    • The recognition mechanism conferring α6β1 selectivity was not elucidated
    • Whether RAB11FIP5 directly contacts integrin cytoplasmic tails was unknown
11. 2020 Medium

    Showing that RAB11FIP5 promotes lysosomal degradation of KSHV ORF45 and restricts viral particle release revealed an antiviral function mediated by diverting a viral protein from productive trafficking.

    Evidence Co-immunoprecipitation, overexpression/knockdown, viral particle quantification, lysosomal inhibition assays

    PMID:33315947

    Open questions at the time

    • Whether endogenous RAB11FIP5 levels are sufficient to restrict KSHV in physiological infection was not tested
    • Mechanism by which RAB11FIP5 redirects ORF45 to lysosomes was not defined
12. 2021 Medium

    Discovery that TRIM21-mediated K6-polyubiquitination activates RAB11FIP5 for pIgA transcytosis, and that RAB11FIP5 acts additively with FIP1, defined a non-degradative ubiquitin signal controlling transcytotic function.

    Evidence Ubiquitination assays, siRNA knockdown, immunoprecipitation, and transcytosis assays in polarized epithelial cells

    PMID:34638806

    Open questions at the time

    • The ubiquitinated lysine residue(s) on RAB11FIP5 were not mapped
    • How K6-polyubiquitin alters RAB11FIP5 interactions or membrane association was not resolved
13. 2021 Medium

    Demonstrating that RAB11FIP5 binds ephrinB1 and that its loss reduces telencephalon size — rescuable by ephrinB1 overexpression — established a developmental recycling pathway critical for forebrain progenitor proliferation.

    Evidence Co-immunoprecipitation, morpholino knockdown in Xenopus, rescue by ephrinB1, cell proliferation assays

    PMID:33462110

    Open questions at the time

    • Whether this pathway operates in mammalian brain development was not tested
    • Whether RAB11FIP5 is recycled together with ephrinB1 or acts only as a sorting factor was not distinguished

• Key open questions include the structural basis of cargo selectivity among RAB11FIP5-dependent recycling routes, the integration of multiple post-translational modifications (ERK, PKA, TRIM21 ubiquitination) on a single effector molecule, and the mechanism by which RAB11FIP5 selectively supports LTD-associated AMPAR trafficking.
• No structural model of RAB11FIP5 in complex with any cargo or regulatory partner exists
• Crosstalk between phosphorylation and ubiquitination in controlling RAB11FIP5 activity has not been investigated
• Identity of the specific AMPAR trafficking step dependent on RAB11FIP5 in LTD remains undefined