RAB15 is a small GTPase of the Rab family that regulates endocytic membrane trafficking, specifically at the interface between sorting endosomes and the endocytic recycling compartment (ERC). RAB15 localizes to early/sorting endosomes and the perinuclear ERC, where it modulates receptor recycling pathways. In its GTP-bound active state, RAB15 recruits effector proteins including REP15, which specifically localizes to the ERC and regulates slow receptor recycling. Wild-type and GTP-locked RAB15 inhibit both fluid-phase and receptor-mediated endocytosis and reduce homotypic early endosome fusion, counteracting the stimulatory effects of Rab5. RAB15 also participates in regulated exocytosis, cooperating with Rab27a and the shared effector Munc13-4 in Weibel-Palade body secretion in endothelial cells. The protein has been detected at cilia in high-throughput screens, though it is not required for primary cilium formation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006887 exocytosis | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation based on phylogenetic inference. RAB15 has been directly shown to participate in Weibel-Palade body exocytosis in endothelial cells, where it cooperates with Rab27a and the effector Munc13-4 to drive secretion [PMID:22899725]. Reason: The IBA annotation is well-supported by experimental data. PMID:22899725 demonstrates through complete Rab screening that RAB15 localizes to Weibel-Palade body membranes and knockdown experiments show it is required for WPB exocytosis, cooperating with Rab27a via the shared effector Munc13-4. Supporting Evidence: PMID:22899725 Apart from Rab3 and Rab27, we identified three additional Rabs, Rab15 (a previously reported endocytic Rab), Rab33 and Rab37, on the WPB limiting membrane. A knockdown approach using siRNAs showed that among these five WPB Rabs only Rab3, Rab27 and Rab15 are required for exocytosis. |
| GO:0010008 endosome membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for endosome membrane localization. RAB15 is well-established to localize to early/sorting endosomes and the endocytic recycling compartment [PMID:10837464, PMID:16195351]. Reason: The IBA annotation is strongly supported by primary literature. Multiple studies demonstrate RAB15 localization to early endosome membranes and the ERC through imaging and biochemical fractionation. Supporting Evidence: PMID:16195351 Sorting endosomes and the endocytic recycling compartment are critical intracellular stores for the rapid recycling of internalized membrane receptors to the cell surface in multiple cell types file:human/RAB15/RAB15-deep-research-falcon.md RAB15 localizes to sorting/early endosomes (SEs/EEs) and the perinuclear endocytic recycling compartment (ERC), where it co-resides with Rab4/5 on SEs and Rab11 on ERC |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProt keyword mapping. RAB15 is a small GTPase with a P-loop NTPase domain that binds GTP/GDP as part of its functional cycle. Reason: This is an accurate but general annotation. RAB15 contains conserved GTP-binding motifs (P-loop, switch I/II regions) and the GO:0005525 (GTP binding) annotation provides the more specific function. Both are acceptable. |
| GO:0003924 GTPase activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation based on InterPro domain mapping. RAB15 contains the small GTPase domain (IPR001806) and RAB15-specific domain (IPR041826) which encode GTP hydrolysis activity. Reason: RAB15 has EC:3.6.5.2 assigned based on sequence similarity and domain architecture. The catalytic GTPase activity is fundamental to its function in membrane trafficking, cycling between GTP-bound (active) and GDP-bound (inactive) states. Supporting Evidence: PMID:10837464 To characterize the role of Rab15 in endocytosis, we prepared functional mutants of HArab15 and examined their effects on early endocytic trafficking |
| GO:0003925 G protein activity | IEA GO_REF:0000003 | ACCEPT | Summary: IEA annotation based on EC number mapping (EC:3.6.5.2). RAB15 functions as a small monomeric G protein, cycling between GTP and GDP-bound states. Reason: Accurate annotation. RAB15 is a canonical Rab GTPase with G protein activity, regulated by GEFs and GAPs, and recruits effectors in the GTP-bound state. Supporting Evidence: PMID:10837464 Rab GTPases play an important regulatory role in early endocytosis |
| GO:0005525 GTP binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation based on InterPro and UniProt keyword mapping. RAB15 binds GTP through its conserved P-loop domain and switch regions. Reason: Fundamental molecular function for RAB15. The GTP-bound form is the active state that recruits effector proteins like REP15. Supporting Evidence: PMID:16195351 REP15 interacts directly with Rab15-GTP but not with Rab5 or Rab11 |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location vocabulary. RAB15 is membrane-anchored via C-terminal geranylgeranyl prenylation and localizes to the cytoplasmic face of membranes including the plasma membrane. Reason: UniProt states RAB15 is at the cell membrane, lipid-anchored, cytoplasmic side. RAB15 cycles between cytosol and membranes including the plasma membrane as part of its regulatory role in recycling cargo to the cell surface. |
| GO:0015031 protein transport | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProt keyword mapping. RAB15 regulates vesicular transport of membrane receptors through the endocytic pathway. Reason: Accurate general annotation. RAB15 regulates trafficking of receptors like the transferrin receptor through sorting endosomes and the ERC. Supporting Evidence: PMID:16195351 Rab15 differentially regulates transferrin receptor trafficking through sorting endosomes and the endocytic recycling compartment |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: IEA annotation based on UniProt keyword mapping. As a GTPase (EC:3.6.5.2), RAB15 has hydrolase activity, hydrolyzing GTP to GDP. Reason: While technically correct, this is too general an annotation. The more specific GO:0003924 (GTPase activity) and GO:0003925 (G protein activity) terms capture the actual enzymatic function more precisely. Hydrolase activity alone is uninformative for a Rab GTPase. |
| GO:0032482 Rab protein signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation based on InterPro domain mapping (IPR041826 - Rab15 specific domain). RAB15 functions in Rab-mediated signaling cascades controlling membrane trafficking. Reason: Appropriate annotation for RAB15's role as a regulatory GTPase. RAB15 participates in signaling networks with other Rabs (Rab5, Rab4, Rab11, Rab27) to coordinate membrane trafficking events. Supporting Evidence: PMID:10837464 HArab15 may counteract the reported stimulatory effect of Rab5 on early endocytosis |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: IEA annotation based on UniProt keyword mapping. RAB15 requires Mg2+ as a cofactor for GTP binding and hydrolysis. Reason: The annotation is technically correct but should be more specific. RAB15 specifically binds magnesium ions (Mg2+) as a cofactor for GTPase activity, coordinated at positions T22 and T40 (switch I and P-loop regions). Proposed replacements: magnesium ion binding |
| GO:0003925 G protein activity | IDA PMID:10837464 Rab15 differentially regulates early endocytic trafficking. | ACCEPT | Summary: IDA annotation from Zuk & Elferink 2000 demonstrating RAB15 functions as a regulatory GTPase. Functional mutants (GTP-locked Q67L, GDP-locked T22N, nucleotide-free N121I) were characterized for their effects on endocytosis. Reason: Strong experimental evidence. The paper demonstrates RAB15 GTPase activity through functional characterization of nucleotide-binding mutants and their differential effects on endocytic trafficking. Supporting Evidence: PMID:10837464 Wild-type HArab15 and its constitutively active, GTP-bound mutant (Q67L) reduce fluid phase and receptor-mediated endocytosis without affecting the rate of recycling from early endosomal compartments |
| GO:0006898 receptor-mediated endocytosis | IDA PMID:10837464 Rab15 differentially regulates early endocytic trafficking. | ACCEPT | Summary: IDA annotation from Zuk & Elferink 2000. RAB15 regulates receptor-mediated endocytosis; overexpression of wild-type or GTP-locked RAB15 inhibits receptor-mediated endocytosis, while inactive mutants have differential stimulatory effects. Reason: Well-supported by experimental data. The study demonstrates RAB15 involvement in receptor-mediated endocytosis using transferrin receptor as a model cargo and characterizes how different RAB15 mutants affect this process. Supporting Evidence: PMID:10837464 Inhibition of early endocytosis appears to be due to a reduction in the rate of homotypic early endosome fusion |
| GO:1903307 positive regulation of regulated secretory pathway | IMP PMID:22899725 A complete Rab screening reveals novel insights in Weibel-Pa... | ACCEPT | Summary: IMP annotation from Zografou et al. 2012. siRNA knockdown of RAB15 reduced Weibel-Palade body exocytosis in endothelial cells, demonstrating RAB15 positively regulates this regulated secretory pathway. Reason: Strong experimental evidence from knockdown experiments. RAB15 is required for WPB exocytosis and cooperates with Rab27a via the shared effector Munc13-4. Supporting Evidence: PMID:22899725 A knockdown approach using siRNAs showed that among these five WPB Rabs only Rab3, Rab27 and Rab15 are required for exocytosis |
| GO:1903307 positive regulation of regulated secretory pathway | IGI PMID:22899725 A complete Rab screening reveals novel insights in Weibel-Pa... | ACCEPT | Summary: IGI annotation from Zografou et al. 2012, indicating genetic interaction with RAB27A (UniProtKB:P51159). RAB15 and RAB27A cooperate in WPB exocytosis through the shared effector Munc13-4. Reason: The IGI annotation captures the genetic/functional interaction between RAB15 and RAB27A in regulating WPB exocytosis via their common effector Munc13-4. Supporting Evidence: PMID:22899725 Intriguingly, we found that Rab15 cooperates with Rab27a in WPB secretion |
| GO:0005929 cilium | IDA PMID:17646400 Functional dissection of Rab GTPases involved in primary cil... | REMOVE | Summary: IDA annotation from Yoshimura et al. 2007 based on a systematic screen of Rab localization at primary cilia. However, this paper specifically states that RAB15 was NOT among the Rabs localized to or required for primary cilium formation. Reason: This annotation appears to be an error. PMID:17646400 specifically states that Rab8a is the sole Rab enriched at primary cilia, and that dominant-negative forms of Rab8a, -17, and -23 (but not others including RAB15) prevented primary cilium formation. RAB15 is not mentioned as localizing to cilia in this study. Supporting Evidence: PMID:17646400 Screening the human Rabs revealed that Rab8a was the only Rab that could be detected on primary cilia when expressed as a GFP-tagged protein |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: HDA annotation from high-throughput proteomics study of urinary exosomes. RAB15 was identified among 1132 proteins in urinary exosomes by LC-MS/MS. Reason: This is a high-throughput detection that does not indicate functional localization. Detection in exosomes may reflect packaging of endosomal proteins into exosome vesicles during MVB formation, consistent with RAB15's endosomal localization, but does not represent a core functional localization. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes |
| GO:0005515 protein binding | IPI PMID:16195351 Rab15 effector protein: a novel protein for receptor recycli... | REMOVE | Summary: IPI annotation based on RAB15 interaction with REP15 (UniProtKB:Q6BDI9). Reason: This annotation is uninformative. GO:0005515 (protein binding) does not provide meaningful information about RAB15's molecular function. The specific interaction with REP15 as a Rab effector would be better captured by a more specific term such as GO:0005100 (Rho GTPase activator activity) or annotations at the biological process level for the recycling pathway. Supporting Evidence: PMID:16195351 we identified the novel protein Rab15 effector protein (REP15) as a binding partner for Rab15-GTP |
| GO:0005737 cytoplasm | IDA PMID:16195351 Rab15 effector protein: a novel protein for receptor recycli... | ACCEPT | Summary: IDA annotation for cytoplasmic localization. RAB15 cycles between cytosol (GDP-bound, with GDI) and membrane compartments (GTP-bound, active). Reason: Accurate annotation. Rab GTPases like RAB15 exist in both cytosolic and membrane-bound pools as part of their regulatory cycle. Supporting Evidence: PMID:16195351 REP15 is compartment specific, colocalizing with Rab15 and Rab11 on the endocytic recycling compartment but not with Rab15, Rab4, or early endosome antigen 1 on sorting endosomes |
| GO:0010008 endosome membrane | IDA PMID:16195351 Rab15 effector protein: a novel protein for receptor recycli... | ACCEPT | Summary: IDA annotation for endosome membrane localization from Strick & Elferink 2005. RAB15 localizes to sorting endosomes and the endocytic recycling compartment. Reason: Primary experimental evidence demonstrating RAB15 localization to endosomal membranes through colocalization studies with endosomal markers. Supporting Evidence: PMID:16195351 REP15 is compartment specific, colocalizing with Rab15 and Rab11 on the endocytic recycling compartment but not with Rab15, Rab4, or early endosome antigen 1 on sorting endosomes |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:16195351 Rab15 effector protein: a novel protein for receptor recycli... | ACCEPT | Summary: IDA annotation for perinuclear localization from Strick & Elferink 2005. The endocytic recycling compartment where RAB15 localizes is positioned perinuclearly. Reason: Accurate annotation. The ERC is characteristically located in the perinuclear region, and RAB15 colocalizes there with Rab11 and REP15. Supporting Evidence: PMID:16195351 REP15 is compartment specific, colocalizing with Rab15 and Rab11 on the endocytic recycling compartment |
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Download this section (compressed HTML)Q: What are the specific GEFs and GAPs that regulate RAB15 activity in different cellular contexts?
Q: How does RAB15 coordinate with Rab5, Rab4, and Rab11 at the sorting endosome decision point?
Q: Is the Munc13-4 interaction with RAB15 direct, and what is the structural basis for shared effector recognition with Rab27a?
Q: Does RAB15 have roles in regulated secretion in cell types beyond endothelial cells?
Experiment: Structural determination of RAB15-Munc13-4 complex to understand shared effector recognition
Hypothesis: RAB15 and Rab27a bind overlapping regions of Munc13-4 through conserved Rab-effector interfaces
Experiment: Proximity labeling (BioID/APEX) to identify the complete RAB15 interactome at different membrane compartments
Hypothesis: RAB15 has compartment-specific effector interactions at sorting endosomes versus ERC
Experiment: Live-cell imaging of RAB15 dynamics during cargo sorting decisions at early endosomes
Hypothesis: RAB15 activation state changes during cargo sorting to fast versus slow recycling pathways
Experiment: Generation of RAB15 knockout/knockin cell lines to study endogenous protein function
Hypothesis: RAB15 loss affects recycling of multiple receptor types beyond transferrin receptor
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