The E3 ubiquitin-ligase HACE1 catalyzes the ubiquitylation of active Rac1

Dev Cell. 2011 Nov 15;21(5):959-65. doi: 10.1016/j.devcel.2011.08.015. Epub 2011 Oct 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • RAC1 protein, human
  • Ubiquitin
  • HACE1 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • rac1 GTP-Binding Protein