Affinage

EHBP1L1

EH domain-binding protein 1-like protein 1 · UniProt Q8N3D4

Length
1523 aa
Mass
161.9 kDa
Annotated
2026-06-09
23 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EHBP1L1 is a multidomain adapter that couples Rab GTPase signaling to actin and the membrane-tubulation machinery to direct polarized vesicular transport (PMID:26833786). It directly binds GTP-loaded Rab8 and Bin1/amphiphysin II to form a complex with dynamin at the endocytic recycling compartment, and this Rab8/10–EHBP1L1–Bin1–dynamin axis is required for apical-directed transport in polarized epithelial cells; its loss in mice produces truncated, sparse microvilli and missorting of apical membrane proteins to lysosomes (PMID:26833786). The same axis operates downstream of LRRK2: phosphorylation of Rab8 and Rab10 recruits EHBP1L1 to stressed lysosomes to suppress lysosomal enlargement and promote secretion (PMID:30209220), whereas at macropinosomes EHBP1L1 acts as an effector of non-phosphorylated GTP-bound Rab10 to drive fast recycling tubule formation and cargo turnover, a function that LRRK2 phosphorylation of Rab10 antagonizes (PMID:32853409). Beyond trafficking, EHBP1L1 controls organelle and nuclear positioning: it is required for nuclear polarization during erythroblast enucleation, with its loss causing stomatocytic erythrocytes and anemic lethality, and for correct nuclear/mitochondrial positioning in skeletal muscle (PMID:37042948), and it negatively regulates primary cilium length by localizing CD2AP/CIN85 to the ciliary sheath and remodeling basal-body actin (PMID:36754282). In renal cell carcinoma, EHBP1L1 stabilizes JAK1 by competing with SOCS1, thereby sustaining JAK1/STAT1/PD-L1 signaling and an immunosuppressive microenvironment (PMID:36775874).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2016 High

    Established EHBP1L1 as the molecular bridge linking active Rab8 to the Bin1–dynamin tubulation machinery, defining its core role in apical-directed membrane transport.

    Evidence Biochemical pulldown/Co-IP, knockdown in intestinal organoids, and EHBP1L1-knockout mouse morphology

    PMID:26833786

    Open questions at the time
    • Structural basis of the Rab8/Bin1/dynamin assembly not resolved
    • Whether Rab10 substitutes for Rab8 in this complex not tested here
  2. 2018 High

    Placed EHBP1L1 downstream of LRRK2 signaling, showing phosphorylated Rab8/Rab10 recruit it to stressed lysosomes to control lysosomal size and secretion.

    Evidence Family-wide Rab screen, phosphorylation-dependent recruitment assays, chloroquine lysosomal stress, LRRK2-KO mouse renal tubules

    PMID:30209220

    Open questions at the time
    • Direct effector mechanism at the lysosome membrane not defined
    • Relationship to the ERC trafficking role unclear
  3. 2020 High

    Resolved how Rab10 phosphorylation state gates EHBP1L1 activity, showing it is an effector of non-phosphorylated GTP-Rab10 that drives fast macropinosomal recycling antagonized by LRRK2.

    Evidence Overexpression competition assay, LRRK2 kinase inhibition, Rab10 knockdown, live-cell imaging in primary macrophages/dendritic cells/microglia

    PMID:32853409

    Open questions at the time
    • Quantitative competition between EHBP1L1 binding and LRRK2 phosphorylation not measured
    • Cargo specificity of recycling tubules undefined
  4. 2020 Medium

    Identified EHBP1L1 as a TBC1D1 interactor via its PTB domains, linking it to a Rab-GAP in myotubes independent of AMPK.

    Evidence Unbiased quantitative proteomics Co-IP in C2C12 myotubes with AMPK activation controls

    PMID:33087848

    Open questions at the time
    • Functional consequence of the TBC1D1 interaction not tested
    • No reciprocal validation or in vivo confirmation
  5. 2023 High

    Extended the Rab/Bin1/dynamin axis to nuclear and organelle positioning, showing EHBP1L1 is required for erythroblast nuclear polarization during enucleation and for nuclear/mitochondrial positioning in muscle.

    Evidence Ehbp1l1-knockout mouse analysis, immunofluorescence of organelle positioning, erythrocyte morphology assays

    PMID:37042948

    Open questions at the time
    • Mechanism connecting vesicular transport to nuclear polarization unresolved
    • Whether the muscle phenotype reflects the same molecular pathway untested
  6. 2023 High

    Defined a ciliary function via newly identified CD2AP/CIN85 partners, showing EHBP1L1 restrains cilium length through basal-body actin remodeling.

    Evidence siRNA knockdown, rescue with WT vs CD2AP/CIN85-binding-deficient mutant, cilia length and actin organization assays

    PMID:36754282

    Open questions at the time
    • How CD2AP/CIN85 recruitment couples to actin nucleation not detailed
    • Relationship between ciliary and trafficking roles unclear
  7. 2023 Medium

    Revealed a non-trafficking role in tumor immune evasion, showing EHBP1L1 stabilizes JAK1 by competing with SOCS1 to sustain STAT1/PD-L1 signaling.

    Evidence Co-IP, SOCS1 competitive binding assay, proteasomal degradation assay, knockdown/knockout with immune readouts and PDX models

    PMID:36775874

    Open questions at the time
    • Single lab without independent replication
    • Domain of EHBP1L1 mediating JAK1 binding not mapped
    • Connection to its Rab-effector function unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EHBP1L1's distinct activities — Rab/Bin1/dynamin trafficking, basal-body actin remodeling, and JAK1 stabilization — are partitioned across cell types and integrated by phosphorylation remains unresolved.
  • No structural model of full-length EHBP1L1 with its partners
  • Regulatory phosphosites (e.g. S1443) lack functional validation
  • Tissue-specific partner usage undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005856 cytoskeleton 2 GO:0005764 lysosome 1 GO:0005768 endosome 1 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9609507 Protein localization 1
Partners
BIN1CD2APDNM2JAK1RAB10RAB8ASH3KBP1TBC1D1

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 EHBP1L1 directly binds GTP-loaded Rab8 and Bin1/amphiphysin II, forming a complex with dynamin at the endocytic recycling compartment (ERC). This complex is required for apical-directed transport in polarized epithelial cells; EHBP1L1- or Bin1-depleted or dynamin-inhibited small intestine organoids accumulate apical membrane proteins in lysosomes. EHBP1L1-deficient mice display truncated and sparse microvilli, confirming its role in maintaining the apical plasma membrane. Biochemical pulldown, Co-IP, overexpression and knockdown in organoids, EHBP1L1-knockout mouse analysis, immunofluorescence The Journal of cell biology High 26833786
2018 EHBP1L1 acts as a downstream effector of LRRK2-phosphorylated Rab8 and Rab10 on stressed lysosomes. LRRK2-mediated phosphorylation of Rab8/Rab10 recruits EHBP1L1 (and EHBP1) to overloaded lysosomes, where they mediate suppression of lysosomal enlargement and promotion of lysosomal secretion. Family-wide Rab GTPase screening, phosphorylation-dependent recruitment assays, lysosomal stress model (chloroquine), LRRK2-deficient mouse renal tubule analysis, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 30209220
2020 LRRK2-mediated phosphorylation of Rab10 blocks EHBP1L1-mediated recycling tubules and cargo turnover at macropinosomes in macrophages. EHBP1L1 overexpression competitively inhibits LRRK2 phosphorylation of Rab10 and promotes cargo recycling, mimicking LRRK2 kinase inhibition. Thus EHBP1L1 functions as an effector of non-phosphorylated (GTP-bound) Rab10 to drive fast vesicle recycling from macropinosomes. Overexpression competition assay, LRRK2 kinase inhibition, Rab10 knockdown, live-cell imaging of recycling tubules in mouse and human primary macrophages/dendritic cells/microglia-like cells The EMBO journal High 32853409
2023 EHBP1L1 interacts with and stabilizes JAK1 protein in renal cell carcinoma cells. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, elevating JAK1 levels and activating JAK1/STAT1/PD-L1 signaling to create an immunosuppressive tumor microenvironment. EHBP1L1 depletion reduces JAK1 protein, PD-L1 surface expression, and enhances CD8+ T cell-mediated anti-tumor immunity. Co-immunoprecipitation (EHBP1L1–JAK1 interaction), competitive binding assay with SOCS1, proteasomal degradation assay, EHBP1L1 knockdown/knockout with functional immune readouts, PDX models Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 36775874
2023 EHBP1L1 is required for nuclear polarization during erythroblast enucleation. Ehbp1l1-/- mice show impaired nuclear polarization before enucleation, leading to decreased enucleation efficiency, stomatocytic erythrocyte morphology with dehydration, and early postnatal anemic lethality. EHBP1L1 interactors Rab10, Bin1, and dynamin are also involved in this process, extending the Rab8/10-EHBP1L1-Bin1-dynamin axis to erythropoiesis. EHBP1L1 loss also causes mislocalization of nuclei and mitochondria in skeletal muscle cells, phenocopying centronuclear myopathy. Ehbp1l1-knockout mouse analysis, immunofluorescence for nuclear/organelle positioning, erythrocyte morphology and dehydration assays Blood advances High 37042948
2023 EHBP1L1 and its newly identified interactors CD2AP and CIN85 negatively regulate primary cilia length via actin network remodeling around the basal body. EHBP1L1 is localized to the ciliary sheath and is required for CD2AP/CIN85 localization there. Depletion of EHBP1L1 or CD2AP/CIN85 causes cilia elongation and actin nucleation/branching defects at the ciliary base. A CD2AP/CIN85-binding-deficient EHBP1L1 mutant fails to rescue these phenotypes, demonstrating that the EHBP1L1–CD2AP/CIN85 interaction is mechanistically required. Immunofluorescence microscopy, siRNA knockdown, rescue with WT vs. binding-deficient EHBP1L1 mutant, cilia length measurements, actin organization assays The Journal of biological chemistry High 36754282
2023 In colorectal cancer cells, PD-L1 membrane distribution is mediated by the membrane transport complex Rab8/EHBP1L1, placing EHBP1L1 in a PCSK6/ACVR1B-p300-Rab8/EHBP1L1-PD-L1 signaling axis that controls PD-L1 surface levels. Single-cell sequencing, co-immunoprecipitation, functional rescue/inhibition in tumor cell lines and mouse models Cell death and differentiation Low 41975069
2010 EHBP1L1 (also known as Tangerin) contains a singlet calponin homology (CH) domain capable of actin binding, placing it in the class of multidomain proteins that link actin cytoskeletal organization to vesicular trafficking. Bioinformatic domain analysis (SMART program) and comparative sequence analysis of human singlet CH-domain proteins Molecular biology reports Low 19459066
2020 EHBP1L1 was identified as a TBC1D1-interacting protein in C2C12 myotubes via quantitative proteomics. The interaction occurs through the phosphotyrosine binding (PTB) domains of TBC1D1 and is not regulated by AMPK activation. Unbiased quantitative proteomics Co-IP in C2C12 myotubes, AMPK activation experiments Scientific reports Medium 33087848
2025 S1443 phosphorylation on EHBP1L1 is insulin-responsive in skeletal muscle of aged rats of both sexes, and this phosphosite is associated with insulin-stimulated glucose uptake specifically in females, suggesting EHBP1L1 participates in insulin/GLUT4 trafficking regulation via phosphorylation. Deep phosphoproteomic profiling of rat skeletal muscle with insulin stimulation and calorie restriction interventions The journals of gerontology. Series A, Biological sciences and medical sciences Low 41105193
2022 EHBP1L1 is expressed in rat primary and secondary spermatocytes and localizes with actin in the perinuclear cytoplasm adjacent to the acrosomal and Golgi regions of spermatids during acrosome biogenesis, consistent with a role in vesicular trafficking during this process. Western blot, immunofluorescence, in situ hybridization, RT-PCR on enriched testicular cell fractions Biomedicines Low 35052860

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proceedings of the National Academy of Sciences of the United States of America 249 30209220
2015 A CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma. Nature communications 101 26515236
2014 Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. American journal of human genetics 100 24954895
2020 LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes. The EMBO journal 76 32853409
2016 EHBP1L1 coordinates Rab8 and Bin1 to regulate apical-directed transport in polarized epithelial cells. The Journal of cell biology 53 26833786
2014 Comprehensive replication of the relationship between myopia-related genes and refractive errors in a large Japanese cohort. Investigative ophthalmology & visual science 47 25335978
2023 EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 36 36775874
2021 Lethal variants in humans: lessons learned from a large molecular autopsy cohort. Genome medicine 27 34645488
2020 TBC1D1 interacting proteins, VPS13A and VPS13C, regulate GLUT4 homeostasis in C2C12 myotubes. Scientific reports 16 33087848
2023 EHBP1L1, an apicobasal polarity regulator, is critical for nuclear polarization during enucleation of erythroblasts. Blood advances 12 37042948
2024 Genome-wide DNA methylation profiling in blood reveals epigenetic signature of incident acute coronary syndrome. Nature communications 10 39198424
2022 Differential Expression and Localization of EHBP1L1 during the First Wave of Rat Spermatogenesis Suggest Its Involvement in Acrosome Biogenesis. Biomedicines 10 35052860
2009 Singlet CH domain containing human multidomain proteins: an inventory. Molecular biology reports 10 19459066
2024 Comparative genomics of macaques and integrated insights into genetic variation and population history. bioRxiv : the preprint server for biology 8 38645259
2020 EH domain binding protein 1-like 1 (EHBP1L1), a protein with calponin homology domain, is expressed in the rat testis. Zygote (Cambridge, England) 6 32795384
2023 The Rab GTPase-binding protein EHBP1L1 and its interactors CD2AP/CIN85 negatively regulate the length of primary cilia via actin remodeling. The Journal of biological chemistry 5 36754282
2022 An EHPB1L1 Nonsense Mutation Associated with Congenital Dyserythropoietic Anemia and Polymyopathy in Labrador Retriever Littermates. Genes 5 36011338
2022 Machine learning algorithm-based identification and verification of characteristic genes in acute kidney injury. Frontiers in medicine 5 36313991
2022 EHBP1L1 Frameshift Deletion in English Springer Spaniel Dogs with Dyserythropoietic Anemia and Myopathy Syndrome (DAMS) or Neonatal Losses. Genes 3 36140701
2025 Sex-specific phosphoproteome responses to calorie restriction and insulin in skeletal muscle from older rats. The journals of gerontology. Series A, Biological sciences and medical sciences 2 41105193
2025 Genome-Wide Association Study and Rare Variant Association Studies of Strabismus in the All of Us Research Program. Ophthalmology science 1 40837069
2026 Targeting CAFs-derived PCSK6 inhibits redistribution of PD-L1 and restores response of CD8+T cells against colorectal cancer. Cell death and differentiation 0 41975069
2024 European EHBP1L1 Genotyping Survey of Dyserythropoietic Anemia and Myopathy Syndrome in English Springer Spaniels. Veterinary sciences 0 39728936

Missed literature

Know a paper Affinage missed for EHBP1L1? Flag it for the maintainers and the community.

No submissions yet.