RABIF/MSS4 is a Rab-stabilizing holdase chaperone required for GLUT4 exocytosis
Open accessAbstract
Significance: Rab GTPases are central regulators of vesicle-mediated cargo transport. They are switched from the GDP-bound inactive conformation to the GTP-bound active state by guanine nucleotide exchange factors (GEFs). Rab-interacting factor (RABIF)/mammalian suppressor of Sec4 (MSS4) and its yeast homolog DSS4 are the first putative GEFs isolated for Rabs, but their biological function and molecular mechanism remained unclear. In this work, we demonstrate that RABIF plays a crucial role in exocytosis. Unexpectedly, we discovered that RABIF does not function as a GEF, as previously assumed. Instead, RABIF is a Rab-stabilizing holdase chaperone, a previously unrecognized mode of Rab regulation independent of its GDP-releasing activity. We suggest that a requirement for holdase chaperones is likely a general feature of Rab GTPases.
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GLUT4 depends on general exocytic and endocytic pathways to regulate its surface levels.
“The reporter is based on the glucose transporter GLUT4 (Fig. 1A), which depends on general exocytic and endocytic pathways to regulate its surface levels (3, 19–21).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [19]
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Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation
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Improving CRISPR-Cas nuclease specificity using truncated guide RNAs
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“When delivered into targeted cells, Cas9 and sgRNAs encoded by the library introduced loss-of-function indel mutations through nonhomologous end joining (7, 9, 10, 15, 17, 62, 63).”
BackgroundIdentification and characterization of essential genes in the human genome
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Research works printed but not linked: 2
- [21]Antonescu CN, McGraw TE, Klip A (2014) Reciprocal regulation of endocytosis and metabolism. Cold Spring Harb Perspect Biol 6:a016964.
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The cell biology of systemic insulin function
Tokarz, V. L., MacDonald, P. E., & Klip, A. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201802095 · Cited by 471 · see citing works
“RAB IF/MSS4 is a Rab-stabilizing holdase chaperone required for GLUT4 exocytosis.”
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Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module
Wang, S., Chen, X., Crisman, L., Dou, X., Winborn, C. S., Wan, C., Puscher, H., Yin, Q., Kennedy, M. J., & Shen, J. (2023) · Science Advances · doi:10.1126/sciadv.ade2540 · Cited by 14 · see citing works
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- Authors
- Gulbranson, D. R., Davis, E. M., Demmitt, B. A., Ouyang, Y., Ye, Y., Yu, H., & Shen, J.
- Affiliations
- University of Colorado Boulder (US)
- National Institutes of Health (US)
- Nanjing Normal University (CN)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-09-11
- Volume
- 114
- Issue
- 39
- Pages
- E8224-E8233
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5625932
- OpenAlex
- W2755239475
- Cited by
- 67
- References
- 4
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 10 · 2020: 13 · 2019: 6 · 2018: 9
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (DK095367, GM102217)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- Rab10, Rab GTPases, insulin-stimulated glucose uptake, adipocytes, proteasomal degradation, Rab8, Rab13, vesicle trafficking
- MeSH terms
- Animals, Exocytosis, HeLa Cells, Humans, Adipocytes, Molecular Chaperones, Guanine Nucleotide Exchange Factors, rab GTP-Binding Proteins, Protein Transport, Transport Vesicles, Cell Line, Tumor, Glucose Transporter Type 4, Mice, HEK293 Cells, CRISPR-Cas Systems
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