The hGID GID4 E3 ubiquitin ligase complex targets ARHGAP11A to regulate cell migration
Open accessPreprint — published as 10.26508/lsa.202403046
Abstract
The human CTLH/GID (hGID) complex emerged as an important E3 ligase regulating multiple cellular processes, including cell cycle progression and metabolic activity. However, the range of biological functions controlled by hGID remains unexplored. Here, we show that the hGID substrate receptor GID4 regulates cell growth and migration. Biochemical and cellular assays combined with proximity-dependent biotinylation (BioID2) revealed that the hGID GID4 E3-ligase targets the Rho-GAP ARHGAP11A for degradation. Depletion of GID4 or impeding the GID4 substrate binding pocket impairs motility and directed cell movement, whereas knockdown of ARHGAP11A significantly restores the cell migration defect. We found that GID4 controls cell migration by degrading ARHGAP11A thereby preventing its accumulation at the cell periphery where it inactivates RhoA activity. Together, we identified a unique function for GID4, as well as a wide range of substrate profiles beyond Pro/N-degron motifs, which pave the way for deciphering additional pathways regulated by hGID E3 ligase activity through its GID4 substrate receptor.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
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- Authors
- Bagci, H., Winkler, M., Uliana, F., Boulais, J., Mohamed, W. I., Park, S. L., Côté, J.-F., & Peter, M.
- Affiliations
- ETH Zurich (CH)
- Montreal Clinical Research Institute (CA)
- Corresponding author
- Peter, Matthias
- ORCID
- Venue
- Life Science Alliance
- Publisher
- openRxiv
- Published
- 2023-07-20
- Volume
- 7
- Issue
- 12
- Pages
- e202403046-e202403046
- ISSN
- 2575-1077 (ISSN-L)
- PMC
- PMC11467045
- OpenAlex
- W4403292916
- Cited by
- 19
- References
- 1
- Citations by year
- 2026: 11 · 2025: 4 · 2024: 3 · 2023: 1
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Life Science Alliance (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_179283/1, 183550, 15247, 310030, 126028, 179283, 126029)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- ARHGAP11A, RhoGAP, ubiquitination, proteasomal degradation, cell migration, cell motility, substrate binding pocket, protein-protein interaction
- MeSH terms
- Cell Movement, Humans, Protein Binding, GTPase-Activating Proteins, rhoA GTP-Binding Protein, Ubiquitin-Protein Ligases, Ubiquitination, HEK293 Cells, Proteolysis
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