The hGID GID4 E3 ubiquitin ligase complex targets ARHGAP11A to regulate cell migration.

Autor:	Bagci H; Institute of Biochemistry, Department of Biology, ETH Zürich, Zürich, Switzerland., Winkler M; Institute of Biochemistry, Department of Biology, ETH Zürich, Zürich, Switzerland., Grädel B; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.; Institute of Cell Biology, University of Bern, Bern, Switzerland., Uliana F; Institute of Biochemistry, Department of Biology, ETH Zürich, Zürich, Switzerland., Boulais J; Montreal Clinical Research Institute (IRCM), Montréal, Canada., Mohamed WI; Institute of Biochemistry, Department of Biology, ETH Zürich, Zürich, Switzerland., Park SL; Institute of Biochemistry, Department of Biology, ETH Zürich, Zürich, Switzerland., Côté JF; Montreal Clinical Research Institute (IRCM), Montréal, Canada.; Molecular Biology Programs, Université de Montréal, Montréal, Canada., Pertz O; Institute of Cell Biology, University of Bern, Bern, Switzerland., Peter M; Institute of Biochemistry, Department of Biology, ETH Zürich, Zürich, Switzerland matthias.peter@bc.biol.ethz.ch.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2024 Oct 10; Vol. 7 (12). Date of Electronic Publication: 2024 Oct 10 (Print Publication: 2024).
DOI:	10.26508/lsa.202403046
Abstrakt:	The human CTLH/GID (hGID) complex emerged as an important E3 ligase regulating multiple cellular processes, including cell cycle progression and metabolism. However, the range of biological functions controlled by hGID remains unexplored. Here, we used proximity-dependent biotinylation (BioID2) to identify proteins interacting with the hGID complex, among them, substrate candidates that bind GID4 in a pocket-dependent manner. Biochemical and cellular assays revealed that the hGID GID4 E3 ligase binds and ubiquitinates ARHGAP11A, thereby targeting this RhoGAP for proteasomal degradation. Indeed, GID4 depletion or impeding the GID4 substrate binding pocket with the PFI-7 inhibitor stabilizes ARHGAP11A protein amounts, although it carries no functional N-terminal degron. Interestingly, GID4 inactivation impairs cell motility and directed cell movement by increasing ARHGAP11A levels at the cell periphery, where it inactivates RhoA. Together, we identified a wide range of hGID GID4 E3 ligase substrates and uncovered a unique function of the hGID GID4 E3 ligase regulating cell migration by targeting ARHGAP11A. (© 2024 Bagci et al.)
Databáze:	MEDLINE
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