EHBP1

EHBP1 is a multidomain endosomal adaptor protein that coordinates membrane trafficking with the actin cytoskeleton across diverse cellular contexts, including endocytic recycling, lipophagy, polarized secretion, dendritic morphogenesis, cholesterol metabolism, and ciliary function. Its N-terminal C2 domain binds phosphoinositides for membrane targeting, its central calponin homology (CH) domain binds F-actin, and its C-terminal bMERB domain engages active Rab8/Rab10 GTPases; in the resting state, the bMERB domain auto-inhibits the CH domain, and Rab8 binding relieves this inhibition to enable simultaneous actin and membrane engagement (PMID:32826901). EHBP1 recruits EHD1/EHD2 via NPF motifs to promote GLUT4 recycling and transferrin endocytosis (PMID:14676205, PMID:15247266), forms a Rab10–EHBP1–EHD2 complex required for LC3 recruitment during lipophagy (PMID:28028537), facilitates sortilin-mediated PCSK9 secretion and LDL receptor turnover through retromer complex regulation (PMID:40015280), and participates in neuronal dendritic arborization via syndapin I–Cobl complexes (PMID:38129132). EHBP1 also directs polarized Wnt secretion by competing with Wntless for AP-1 adaptor binding (PMID:39402333) and localizes to the primary cilium in an INPP5E-dependent manner (PMID:41805112).

1. 2003 High

   Identification of EHBP1 as an EHD2-interacting, actin-binding endocytic adaptor established its foundational role in coupling clathrin-mediated endocytosis to the actin cytoskeleton, with knockdown blocking transferrin and GLUT4 internalization.

   Evidence Co-immunoprecipitation, siRNA knockdown, and endocytosis assays in mammalian cells

   PMID:14676205

   Open questions at the time

   • Structural basis for NPF–EH domain interaction not resolved
   • Whether EHBP1 functions beyond endocytosis was unknown
   • In vivo validation in animal models lacking
2. 2004 High

   Demonstration that EHBP1 interacts with EHD1 and is required for insulin-stimulated GLUT4 recycling extended its role from endocytic internalization to regulated exocytic recycling in adipocytes.

   Evidence Co-immunoprecipitation, siRNA knockdown, GLUT4 translocation and hexose transport assays in 3T3-L1 adipocytes

   PMID:15247266

   Open questions at the time

   • Whether Rab GTPases participate in this pathway was unknown
   • Mechanism of insulin-dependent regulation of EHBP1 not addressed
3. 2010 High

   Discovery that the C. elegans ortholog EHBP-1 directly binds RAB-10 and shares its endosomal recycling phenotype established Rab10 as a key upstream regulator of EHBP1 function, conserved across metazoans.

   Evidence Yeast two-hybrid, in vivo colocalization, and genetic loss-of-function in C. elegans

   PMID:20573983

   Open questions at the time

   • Binding interface between Rab10 and EHBP1 unresolved
   • Whether this interaction is direct in mammalian cells not yet tested
4. 2013 Medium

   Genetic analysis in Drosophila showed that EHBP1 controls Scabrous exocytosis during photoreceptor fate determination, revealing a role in developmental signaling cargo secretion beyond constitutive recycling.

   Evidence Genetic loss-of-function in Drosophila with photoreceptor fate and Scabrous trafficking analysis

   PMID:23788431

   Open questions at the time

   • Molecular mechanism of EHBP1 in exocytic cargo sorting not defined
   • Not confirmed in mammalian developmental contexts
   • Single laboratory study
5. 2016 High

   Identification of a Rab10–EHBP1–EHD2 complex on autophagic membranes at lipid droplets demonstrated that EHBP1 functions in selective autophagy (lipophagy), linking it to LC3 recruitment and lipid droplet engulfment in hepatocytes.

   Evidence siRNA knockdown, dominant-negative Rab10, immunofluorescence, and lipid droplet accumulation assay in hepatocytes

   PMID:28028537

   Open questions at the time

   • How EHBP1 connects to autophagosomal machinery mechanistically unclear
   • Whether lipophagy role extends to other cell types not tested
6. 2020 High

   Crystal structures of the auto-inhibited CH:bMERB complex and the activating bMERB:Rab8 complex revealed the allosteric switch mechanism: Rab8 binding to the bMERB domain displaces the CH domain, enabling actin binding and membrane tubulation, providing the first structural framework for EHBP1 regulation.

   Evidence X-ray crystallography, structure-based mutagenesis, liposome binding, and membrane tubulation reconstitution in vitro

   PMID:32826901

   Open questions at the time

   • Whether auto-inhibition is regulated by post-translational modifications unknown
   • In vivo validation of the structural switch in trafficking contexts not performed
7. 2024 High

   Discovery that EHBP1 forms ternary complexes with syndapin I and the actin nucleator Cobl at dendritic branch sites established a neuronal-specific function for EHBP1 in dendritic arborization, mediated by a chordata-specific syndapin-binding motif.

   Evidence Co-immunoprecipitation, domain mutagenesis, loss- and gain-of-function with rescue in rat hippocampal neurons, live imaging

   PMID:38129132

   Open questions at the time

   • Whether this complex is regulated by Rab GTPases is unknown
   • Relevance to neurodevelopmental disease not established
8. 2024 Medium

   Demonstration that EHBP1 competes with Wntless for AP-1 adaptor complex binding to redirect Wnt/Wingless secretion apically revealed a new mechanism by which EHBP1 acts as a directional switch for polarized cargo sorting.

   Evidence Genetic epistasis in Drosophila, Co-IP competition assay for AP-1 binding, domain deletion analysis

   PMID:39402333

   Open questions at the time

   • Conservation of AP-1 competition mechanism in vertebrate Wnt secretion untested
   • Single laboratory study
   • Whether bMERB coiled-coil motif mediates AP-1 binding directly or indirectly unclear
9. 2025 Medium

   Mechanistic dissection in C. elegans showed that EHBP-1 captures RAB-10-positive lipoprotein exocytic carriers via its coiled-coil and C2 domains, delivering them to recycling endosomes with downstream exocyst involvement, establishing a RAB-10–EHBP-1–exocyst axis in exocytic trafficking.

   Evidence Genetic epistasis, live imaging, domain deletion and GEF identification in C. elegans

   PMID:39702707

   Open questions at the time

   • Whether this exocytic capture mechanism is conserved in mammalian cells unknown
   • Direct biochemical reconstitution of the capture step not performed
10. 2025 High

    Discovery that EHBP1 promotes sortilin-mediated PCSK9 secretion via retromer stabilization linked EHBP1 to cholesterol metabolism and MASH fibrosis; EHBP1 deficiency disrupted retromer localization, increasing hepatic LDLR levels and downstream fibrogenic TAZ signaling.

    Evidence In vivo loss- and gain-of-function in mice on MASH diet, PCSK9 secretion, LDLR, retromer localization, and TAZ assays

    PMID:40015280

    Open questions at the time

    • Direct physical interaction between EHBP1 and retromer subunits not demonstrated
    • Whether this is Rab10-dependent in hepatocytes not addressed
11. 2026 Medium

    Localization of EHBP1 to the basal body and ciliary compartment, dependent on INPP5E phosphoinositide regulation, placed EHBP1 in a ciliary functional module with potential relevance to ciliopathies.

    Evidence BioID proximity labeling, immunofluorescence in fibroblasts/RPE/retinal organoids, INPP5E knockout and patient mutations

    PMID:41805112

    Open questions at the time

    • Functional role of EHBP1 at the cilium not established
    • Whether EHBP1 loss causes ciliary defects not tested
    • Single laboratory study

• The mechanism by which EHBP1 integrates its multiple domain-level activities (C2, CH, bMERB, NPF) to select among distinct trafficking routes — endocytic recycling, lipophagy, polarized secretion, retromer-dependent sorting, and ciliary targeting — in a context-dependent manner remains unresolved.
• No unified model explaining pathway selectivity across cell types
• Post-translational regulation of EHBP1 function unexplored
• Full interactome in mammalian cells not systematically mapped