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PMID:22036506

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Citation

Torrino, S, Visvikis, O, Doye, A, Boyer, L, Stefani, C, Munro, P, Bertoglio, J, Gacon, G, Mettouchi, A and Lemichez, E (2011) The E3 ubiquitin-ligase HACE1 catalyzes the ubiquitylation of active Rac1. Dev. Cell 21:959-65

Abstract

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.

Links

PubMed Online version:10.1016/j.devcel.2011.08.015

Keywords

Animals; Biocatalysis; CHO Cells; Cells, Cultured; Cricetinae; HEK293 Cells; Humans; Proteasome Endopeptidase Complex/metabolism; Ubiquitin/metabolism; Ubiquitin-Protein Ligases/biosynthesis; Ubiquitin-Protein Ligases/metabolism; Ubiquitination; rac1 GTP-Binding Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:RAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IYU2

F

Seeded From UniProt

complete

HUMAN:HACE1

involved_in

GO:0030334: regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HACE1

involved_in

GO:0016601: Rac protein signal transduction

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HACE1

involved_in

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HACE1

enables

GO:0031267: small GTPase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P63000

F

Seeded From UniProt

complete

HUMAN:HACE1

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HACE1

involved_in

GO:0070936: protein K48-linked ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RAC1

enables

GO:0005525: GTP binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RAC1

involved_in

GO:0030334: regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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