Affinage

RABGAP1L

Rab GTPase-activating protein 1-like, isoform 10 · UniProt B7ZAP0

Length
253 aa
Mass
29.0 kDa
Annotated
2026-06-10
20 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RABGAP1L (TBC1D18) is a TBC-domain Rab GTPase-activating protein that governs endosomal maturation and trafficking by inactivating multiple Rab GTPases, thereby linking membrane traffic to cell migration and cell-autonomous immunity (PMID:36197338, PMID:27718357). It is recruited to PI3P-positive early endosomes through direct binding to ankyrin-B, where it inactivates Rab22A to drive polarized recycling of α5β1-integrin to the leading edge of migrating fibroblasts (PMID:27718357). Acting as a Rab5-GAP in association with Mon1, it inactivates Rab5 to promote endosome maturation and endocytic cargo degradation, rescuing the maturation defects of Mon1-deficient cells (PMID:36197338). During defense against Group A Streptococcus it inactivates Rab7A and Rab10 to balance selective autophagy against Rab11A-dependent bacterial expulsion (PMID:40244851). RABGAP1L is also an interferon-stimulated gene that acts as an antiviral restriction factor: its catalytically active TBC domain is required to disrupt endosomal function and block a post-attachment, pre-fusion step of influenza A virus and other endocytosis-dependent RNA virus entry, while entry-promiscuous SARS-CoV-2 escapes restriction (PMID:35320721).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2000 Medium

    Established the gene's existence and an initial expression pattern, asking where an uncharacterized protein with a putative PTB domain operates.

    Evidence Expression gene trapping with lacZ reporter and in vitro hematopoietic differentiation on OP9 stroma, plus gene-trap mice

    PMID:10585558

    Open questions at the time
    • No molecular function assigned
    • PTB domain identified computationally, not functionally tested
    • No Rab substrate or trafficking role established
  2. 2016 High

    Defined RABGAP1L as a Rab22A-inactivating GAP recruited by ankyrin-B to PI3P endosomes, connecting it for the first time to directed cell migration.

    Evidence Co-IP, live imaging, subcellular fractionation and dominant-negative/overexpression rescue in mouse embryonic fibroblasts

    PMID:27718357

    Open questions at the time
    • Whether other Rabs are targeted in this context not resolved
    • Structural basis of AnkB recruitment unknown
    • Restricted to fibroblast migration system
  3. 2022 High

    Identified RABGAP1L (TBC1D18) as a Rab5-GAP acting with Mon1 to drive endosome maturation, showing Rab5 hyperactivation rather than Rab7 loss underlies the Mon1-KO defect.

    Evidence Systematic TBC-domain GAP screen, KO/KD and rescue cell lines, live imaging and Co-IP with Mon1

    PMID:36197338

    Open questions at the time
    • Mechanism of Mon1-dependent recruitment not detailed
    • Relationship between Rab5 and Rab22A activities in the same cell unresolved
  4. 2022 High

    Established RABGAP1L as an interferon-stimulated antiviral restriction factor whose TBC catalytic activity blocks endocytic virus entry, linking its GAP function to innate antiviral defense.

    Evidence RNAi screen, TBC catalytic-mutant overexpression, BioID interactome, endosome function and viral entry-stage assays across multiple viruses

    PMID:35320721

    Open questions at the time
    • Specific Rab substrate driving antiviral restriction not pinned down
    • Mechanism distinguishing endosome-dependent versus promiscuous viruses incomplete
  5. 2025 High

    Dissected dual Rab7A and Rab10 inactivation by RABGAP1L in anti-bacterial cell-autonomous immunity, explaining how it toggles between autophagy and bacterial expulsion.

    Evidence Confocal microscopy, ATG7/ATG5 knockout cells, GAS infection model with overexpression/knockdown and Rab7A/Rab10 functional assays

    PMID:40244851

    Open questions at the time
    • How substrate Rab selection is regulated across contexts unknown
    • Direct GAP assays on Rab7A/Rab10 not shown
    • In vivo relevance to infection outcome untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RABGAP1L selects among its multiple Rab substrates (Rab5, Rab22A, Rab7A, Rab10) in a context-specific manner, and the structural/regulatory basis of its recruitment, remain unresolved.
  • No structural model of substrate engagement
  • Determinants of context-dependent Rab targeting unknown
  • Upstream regulation of GAP activity uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4
Localization
GO:0005768 endosome 3
Pathway
R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ANK2MON1A

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 AnkB (ankyrin-B) binds directly to RabGAP1L and recruits it to PI3P-positive early endosomes, where RabGAP1L inactivates Rab22A, promoting polarized trafficking of α5β1-integrin to the leading edge of migrating fibroblasts. Co-immunoprecipitation, live-cell imaging, subcellular fractionation, dominant-negative/overexpression rescue in mouse embryonic fibroblasts eLife High 27718357
2022 TBC1D18 (RABGAP1L) is a Rab5-GAP that inactivates Rab5 to promote endosome maturation; it associates with Mon1 and localizes near lysosomes in a Mon1-dependent manner. Rab5 hyperactivation (not solely Rab7 loss) underlies the endosome maturation defects in Mon1-KO cells, and TBC1D18 expression rescues these defects while its depletion attenuates endosome formation and endocytic cargo degradation. Comprehensive TBC-domain GAP screen, KO/KD cell lines, rescue experiments, live imaging, co-immunoprecipitation with Mon1 The Journal of cell biology High 36197338
2022 RABGAP1L is an interferon-stimulated gene whose catalytically active TBC domain is required for antiviral activity; it associates with endosomal sorting/maturation/trafficking proteins and its overexpression disrupts endosomal function during influenza A virus (IAV) infection, blocking a post-attachment, pre-fusion step of IAV endocytic entry. Other endocytosis-dependent RNA viruses are also restricted, while SARS-CoV-2 (entry-promiscuous) is resistant. RNAi screen, overexpression with TBC-domain catalytic mutants, proximity interactome (BioID), endosome function assays, viral entry stage analysis Cell reports High 35320721
2025 RabGAP1L modulates cell-autonomous immunity against Group A Streptococcus by inactivating two distinct Rab GTPases: it inactivates Rab7A (which positively regulates selective autophagy via endolysosomal trafficking) and Rab10 (which, together with Rab7A, negatively regulates bacterial expulsion by inhibiting Rab11A-positive recycling endosome formation). When autophagy is deficient (ATG7/ATG5 KO), RabGAP1L-dependent Rab10 inactivation promotes bacterial expulsion via the endocytic recycling pathway. Confocal microscopy, ATG7/ATG5 knockout cells, GAS infection model, overexpression and knockdown of RabGAP1L, Rab7A and Rab10 functional assays Cell reports High 40244851
2000 The mouse ortholog Hhl (RABGAP1L) encodes a novel protein containing a putative phosphotyrosine-binding (PTB) domain and is expressed in a tissue-specific manner in hematopoietic cells (megakaryocytes, CFU-GEMM, BFU-E), as identified by expression gene trapping in ES cells differentiated on OP9 stromal cells. Expression gene trapping with lacZ reporter, in vitro hematopoietic differentiation on OP9, in vivo analysis of gene trap mice Mechanisms of development Medium 10585558

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Performance of two commonly used angiotensin-converting enzyme inhibition assays using FA-PGG and HHL as substrates. The Journal of dairy research 64 16476177
2016 Ankyrin-B is a PI3P effector that promotes polarized α5β1-integrin recycling via recruiting RabGAP1L to early endosomes. eLife 31 27718357
2013 Deletion variants of RABGAP1L, 10q21.3, and C4 are associated with the risk of systemic lupus erythematosus in Korean women. Arthritis and rheumatism 29 23335107
2000 Gene trapping of two novel genes, Hzf and Hhl, expressed in hematopoietic cells. Mechanisms of development 27 10585558
2022 TBC1D18 is a Rab5-GAP that coordinates endosome maturation together with Mon1. The Journal of cell biology 23 36197338
2022 Restriction factor screening identifies RABGAP1L-mediated disruption of endocytosis as a host antiviral defense. Cell reports 16 35320721
2020 Isolation and identification of bioactive peptides from Xuanwei ham that rescue oxidative stress damage induced by alcohol in HHL-5 hepatocytes. Food & function 15 33057513
2017 Arsenic Induces Thioredoxin 1 and Apoptosis in Human Liver HHL-5 Cells. Biological trace element research 14 28512695
2009 RABGAP1L gene rearrangement resulting from a der(Y)t(Y;1)(q12;q25) in acute myeloid leukemia arising in a child with Klinefelter syndrome. Virchows Archiv : an international journal of pathology 12 19184099
2001 Growth of Pseudomonas aureofaciens PGS12 and the Dynamics of HHL and Phenazine Production in Liquid Culture, on Nutrient Agar, and on Plant Roots. Microbial ecology 12 12032605
2017 Therapeutic drug monitoring of amlodipine and the Z-FHL/HHL ratio: Adherence tools in patients referred for apparent treatment-resistant hypertension. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde 8 29022534
2019 Effect of the Plastein Reaction in Presence of Extrinsic Amino Acids on the Protective Activity of Casein Hydrolysate against Ethanol-Induced Damage in HHL-5 Cells. Foods (Basel, Switzerland) 6 30934930
2004 Reduced KIAA0471 mRNA expression in Alzheimer's patients: a new candidate gene product linked to the disease? Human molecular genetics 6 15367492
2022 Isolation and Identification of Antioxidative Peptide from Goose Liver Hydrolysate to Ameliorate Alcohol-Mediated Oxidative Stress Damage in HHL-5 Hepatocytes. Molecules (Basel, Switzerland) 5 36363978
2025 RabGAP1L modulates Rab7A and Rab10 to orchestrate cell-autonomous immunity. Cell reports 4 40244851
2025 "Hyphae Intertwined, Biomolecules Co-Born"-New Polyketides Induction by Co-Culture of the Mangrove Endophytic Fungus Phomopsis asparagi DHS-48 and Pestalotiopsis sp. HHL-101 at Both Volatile and Non-Volatile Levels. Marine drugs 1 41440886
2025 Transcriptome profiling and DNA methylation analysis of human hepatocyte cell line HHL-16 in response to aflatoxin B1. Chemico-biological interactions 0 40288432
2025 Effects of compound fermentation with Limosilactobacillus fermentum HHL-5 and citric acid on wilted king grass silage. Frontiers in veterinary science 0 41180241
2006 [Negative regulation on PCA production is not correlated with positive regulation on BHL and HHL synthesis by gacA in Pseudomonas sp. M18]. Wei sheng wu xue bao = Acta microbiologica Sinica 0 16933626
1993 Endothelial denudation in HHL-rabbit aortas. VASA. Zeitschrift fur Gefasskrankheiten 0 8322499

Missed literature

Know a paper Affinage missed for RABGAP1L? Flag it for the maintainers and the community.

No submissions yet.