title: Autophagy plays a critical role in the degradation of active RHOA, the control of cell cytokinesis, and genomic stability.
abstract: 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.
authors.affiliation: Institute of Research on Cancer and Ageing of Nice (IRCAN), INSERM U1081, CNRS UMR7284, Laboratoire TIRO-MATOs UMR E4320, Commissariat à l'Energie Atomique, Centre Antoine Lacassagne, Avenue de Valombrose; 06107 Nice Cedex 02, France.
authors.forename: Amine
authors.initials: A
authors.lastname: Belaid
authors.forename: Michaël
authors.initials: M
authors.lastname: Cerezo
authors.forename: Abderrahman
authors.initials: A
authors.lastname: Chargui
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Corcelle-Termeau
authors.forename: Florence
authors.initials: F
authors.lastname: Pedeutour
authors.forename: Sandy
authors.initials: S
authors.lastname: Giuliano
authors.forename: Marius
authors.initials: M
authors.lastname: Ilie
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rubera
authors.forename: Michel
authors.initials: M
authors.lastname: Tauc
authors.forename: Sophie
authors.initials: S
authors.lastname: Barale
authors.forename: Corinne
authors.initials: C
authors.lastname: Bertolotto
authors.forename: Patrick
authors.initials: P
authors.lastname: Brest
authors.forename: Valérie
authors.initials: V
authors.lastname: Vouret-Craviari
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
authors.forename: Georges F
authors.initials: GF
authors.lastname: Carle
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.forename: Baharia
authors.initials: B
authors.lastname: Mograbi
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D048749:Cytokinesis / Q000235:genetics / Q000502:physiology*; D042822:Genomic Instability; D015726:Giant Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D059748:Proteolysis; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D025262:Vacuolar Proton-Translocating ATPases; D020742:rhoA GTP-Binding Protein