title: Fine-tuning of actin dynamics by the HSPB8-BAG3 chaperone complex facilitates cytokinesis and contributes to its impact on cell division.
abstract: The small heat shock protein HSPB8 and its co-chaperone BAG3 are proposed to regulate cytoskeletal proteostasis in response to mechanical signaling in muscle cells. Here, we show that in dividing cells, the HSPB8-BAG3 complex is instrumental to the accurate disassembly of the actin-based contractile ring during cytokinesis, a process required to allow abscission of daughter cells. Silencing of HSPB8 markedly decreased the mitotic levels of BAG3 in HeLa cells, supporting its crucial role in BAG3 mitotic functions. Cells depleted of HSPB8 were delayed in cytokinesis, remained connected via a disorganized intercellular bridge, and exhibited increased incidence of nuclear abnormalities that result from failed cytokinesis (i.e., bi- and multi-nucleation). Such phenotypes were associated with abnormal accumulation of F-actin at the intercellular bridge of daughter cells at telophase. Remarkably, the actin sequestering drug latrunculin A, like the inhibitor of branched actin polymerization CK666, normalized F-actin during cytokinesis and restored proper cell division in HSPB8-depleted cells, implicating deregulated actin dynamics as a cause of abscission failure. Moreover, this HSPB8-dependent phenotype could be corrected by rapamycin, an autophagy-promoting drug, whereas it was mimicked by drugs impairing lysosomal function. Together, the results further support a role for the HSPB8-BAG3 chaperone complex in quality control of actin-based structure dynamics that are put under high tension, notably during cell cytokinesis. They expand a so-far under-appreciated connection between selective autophagy and cellular morphodynamics that guide cell division.
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.|Oncology, Centre de recherche du CHU de Québec-Université Laval, Québec, G1R 3S3, Canada.
authors.forename: Alice Anaïs
authors.initials: AA
authors.lastname: Varlet
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.|Oncology, Centre de recherche du CHU de Québec-Université Laval, Québec, G1R 3S3, Canada.
authors.forename: Margit
authors.initials: M
authors.lastname: Fuchs
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.|Oncology, Centre de recherche du CHU de Québec-Université Laval, Québec, G1R 3S3, Canada.
authors.forename: Carole
authors.initials: C
authors.lastname: Luthold
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.|Oncology, Centre de recherche du CHU de Québec-Université Laval, Québec, G1R 3S3, Canada.
authors.forename: Herman
authors.initials: H
authors.lastname: Lambert
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.|Oncology, Centre de recherche du CHU de Québec-Université Laval, Québec, G1R 3S3, Canada.|Département de Biologie Moléculaire, Biochimie Médicale et Pathologie Université Laval, Québec, G1V OA6, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Landry
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Québec, Canada. josee.lavoie@crchudequebec.ulaval.ca.|Oncology, Centre de recherche du CHU de Québec-Université Laval, Québec, G1R 3S3, Canada. josee.lavoie@crchudequebec.ulaval.ca.|Département de Biologie Moléculaire, Biochimie Médicale et Pathologie Université Laval, Québec, G1V OA6, Canada. josee.lavoie@crchudequebec.ulaval.ca.
authors.forename: Josée N
authors.initials: JN
authors.lastname: Lavoie
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000032:analysis / Q000378:metabolism; D000199:Actins / Q000032:analysis / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism*; D002455:Cell Division; D048749:Cytokinesis; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases
keywords: Actin; Autophagy; BAG3; Cytokinesis; HSPB8