Analyse fonctionnelle du remodelage des structures à base d'actine qui dirigent la division cellulaire par le complexe chaperon HSPB8-BAG3

Authors: Varlet, Alice-Anaïs
Advisor: Lavoie, Josée
Abstract: Changes in cell shape are essential to key cellular processes that determine the cell fate, including cell division. They are orchestrated by the remodeling of mechanosensitive actin-based structures guiding cellular tension. Recent data suggest that protein quality control may contribute to the spatiotemporal remodeling of actin-based structures through protein sequestration, recycling and degradation mechanisms. Incidentally, the molecular chaperones of the HSPB family appearas modulatorof actin-based structures under physiological processes. These proteins are known to sequester damaged cellular constituents to prevent their toxic aggregation during proteotoxic stress. Whilst their implications in human pathologies have been clearly established, their mode of action is still poorly understood. The work presented in this thesis addresses the central hypothesis that the chaperone complex formed by HSPB8 and its co-chaperone BAG3 would facilitate the remodeling of actin-based structures, which is deemed instrumental for proper mitotic progression. We have shown that during mitosis, BAG3, in a manner requiring its association with HSPB8, facilitates mitotic rounding, spindle positioning and accurate chromosomes segregation. We further showed that depletion of HSPB8 or BAG3 silencing also interferes with disassembly of the contractile actomyosin ringduring cytokinesis, thereby impairing daughter cells abscission. Such an effect is correlated with accumulation of multinucleated cells, a defect which is corrected by drugs that normalize actin dynamics in HSPB8-depleted cells. These results established a cause-effect relationship between deregulation of actin dynamics and the cell division defects induced by HSPB8 silencing. Further, we found that such a phenotypecan be rescued by rapamycin, a drug that stimulates autophagy, while itis recapitulated in control cells by inhibitors of autophagic degradation. These results, and others presented in this thesis, suggest that the regulation of cell shape remodellingby HSPB8-BAG3 may involve their function in the selective targeting of proteins for autophagic degradation. Finally, evidence was obtained that during mitosis, like during cytokinesis, HSPB8-BAG3 would act by limiting branched actin polymerization. We found that HSPB8-BAG3 can modulate mitotic rounding and the dynamics of an Arp2/3-dependent subcortical actin pool that contributes to spindle positionning, by restrictingthe activity of HDAC6 deacetylase maybe on its target cortactin, both having a role in selective autophagy processes. Together, this work contributed to a better understanding of the mechanisms by which the chaperone complex HSPB8-BAG3 would facilitate transitions in cellshape during cell division and uncovered novel targets of HSPB8-BAG3 that may be implicated in the development of human disorders associated with deregulation of the chaperon complex, notably cancer.
Document Type: Thèse de doctorat
Issue Date: 2018
Open Access Date: 12 July 2019
Grantor: Université Laval
Collection:Thèses et mémoires

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