Autophagy plays a critical role in the degradation of active RHOA, the control of cell cytokinesis, and genomic stability. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Cancer Research Année : 2013

Autophagy plays a critical role in the degradation of active RHOA, the control of cell cytokinesis, and genomic stability.

Amine Belaid
  • Fonction : Auteur
Michaël Cerezo
  • Fonction : Auteur
Abderrahman Chargui
  • Fonction : Auteur
Elisabeth Corcelle-Termeau
  • Fonction : Auteur
Florence Pedeutour
Sandy Giuliano
  • Fonction : Auteur
Corinne Bertolotto
  • Fonction : Auteur
Daniel J Klionsky
  • Fonction : Auteur

Résumé

Degradation of signaling proteins is one of the most powerful tumor-suppressive mechanisms by which a cell can control its own growth. Here, we identify RHOA as the molecular target by which autophagy maintains genomic stability. Specifically, inhibition of autophagosome degradation by the loss of the v-ATPase a3 (TCIRG1) subunit is sufficient to induce aneuploidy. Underlying this phenotype, active RHOA is sequestered via p62 (SQSTM1) within autolysosomes and fails to localize to the plasma membrane or to the spindle midbody. Conversely, inhibition of autophagosome formation by ATG5 shRNA dramatically increases localization of active RHOA at the midbody, followed by diffusion to the flanking zones. As a result, all of the approaches we examined that compromise autophagy (irrespective of the defect: autophagosome formation, sequestration, or degradation) drive cytokinesis failure, multinucleation, and aneuploidy, processes that directly have an impact upon cancer progression. Consistently, we report a positive correlation between autophagy defects and the higher expression of RHOA in human lung carcinoma. We therefore propose that autophagy may act, in part, as a safeguard mechanism that degrades and thereby maintains the appropriate level of active RHOA at the midbody for faithful completion of cytokinesis and genome inheritance.

Dates et versions

hal-00912953 , version 1 (02-12-2013)

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Citer

Amine Belaid, Michaël Cerezo, Abderrahman Chargui, Elisabeth Corcelle-Termeau, Florence Pedeutour, et al.. Autophagy plays a critical role in the degradation of active RHOA, the control of cell cytokinesis, and genomic stability.. Cancer Research, 2013, 73 (14), pp.4311-22. ⟨10.1158/0008-5472.CAN-12-4142⟩. ⟨hal-00912953⟩
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