The E3 Ubiquitin-Ligase HACE1 Catalyzes the Ubiquitylation of Active Rac1

Rac1 small GTPase controls essential aspects of cell biology and is a direct target of numerous bacterial virulence factors. The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain co...

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Bibliographic Details
Published in:Developmental cell 2011-11, Vol.21 (5), p.959-965
Main Authors: Torrino, Stéphanie, Visvikis, Orane, Doye, Anne, Boyer, Laurent, Stefani, Caroline, Munro, Patrick, Bertoglio, Jacques, Gacon, Gérard, Mettouchi, Amel, Lemichez, Emmanuel
Format: Article
Language:English
Subjects:
Animals
Biocatalysis
Biological and medical sciences
Cell differentiation, maturation, development, hematopoiesis
Cell physiology
Cells, Cultured
CHO Cells
Cricetinae
Fundamental and applied biological sciences. Psychology
HEK293 Cells
Humans
Molecular and cellular biology
Proteasome Endopeptidase Complex - metabolism
rac1 GTP-Binding Protein - metabolism
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - biosynthesis
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary:Rac1 small GTPase controls essential aspects of cell biology and is a direct target of numerous bacterial virulence factors. The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation. HACE1 expression increases the ubiquitylation of Rac1, when the GTPase is activated by point mutations or by the GEF-domain of Dbl. RNAi-mediated depletion of HACE1 blocks the ubiquitylation of active Rac1 and increases GTP-bound Rac1 cellular levels. HACE1 antagonizes cell isotropic spreading, a hallmark of Rac1 activation, and is required for endothelial cell monolayer invasion by bacteria. Together, these data establish the role of the HACE1 E3 ubiquitin-ligase in controlling Rac1 ubiquitylation and activity. [Display omitted] ► HACE1 controls ubiquitin/proteasome degradation of active Rac1 ► HACE1 binds and ubiquitylates GTP-bound Rac1 ► HACE1 controls Rac1 activity in cells
ISSN:1534-5807
1878-1551
DOI:10.1016/j.devcel.2011.08.015