CDK1-Mediated Phosphorylation of BAG3 Promotes Mitotic Cell Shape Remodeling and the Molecular Assembly of Mitotic p62 Bodies.

Carole Luthold,Marc-Antoine Rodrigue,Alice-Anaïs Varlet,Amélie Fradet-Turcotte,Solenn M Guilbert,Herman Lambert,Josée N Lavoie,Margit Fuchs

doi:10.3390/cells10102638

Carole Luthold, Marc-Antoine Rodrigue + Show 6 more

Open Access

https://doi.org/10.3390/cells10102638

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Journal: Cells	Publication Date: Oct 2, 2021
Citations: 4	License type: CC BY 4.0

Affiliation: Université Laval, Hôtel-Dieu de Québec

Abstract

The cochaperone BCL2-associated athanogene 3 (BAG3), in complex with the heat shock protein HSPB8, facilitates mitotic rounding, spindle orientation, and proper abscission of daughter cells. BAG3 and HSPB8 mitotic functions implicate the sequestosome p62/SQSTM1, suggesting a role for protein quality control. However, the interplay between this chaperone-assisted pathway and the mitotic machinery is not known. Here, we show that BAG3 phosphorylation at the conserved T285 is regulated by CDK1 and activates its function in mitotic cell shape remodeling. BAG3 phosphorylation exhibited a high dynamic at mitotic entry and both a non-phosphorylatable BAG3T285A and a phosphomimetic BAG3T285D protein were unable to correct the mitotic defects in BAG3-depleted HeLa cells. We also demonstrate that BAG3 phosphorylation, HSPB8, and CDK1 activity modulate the molecular assembly of p62/SQSTM1 into mitotic bodies containing K63 polyubiquitinated chains. These findings suggest the existence of a mitotically regulated spatial quality control mechanism for the fidelity of cell shape remodeling in highly dividing cells.

Highlights

We found that the BCL2-associated athanogene 3 (BAG3) phosphorylation state and HSPB8 regulate the molecular assembly of p62 into dynamic mitotic bodies
We identify BAG3 as a bona fide substrate of CDK1 that collaborates with its chaperone partner HSPB8 to regulate the molecular assembly of p62 into high-ordered mitotic inclusion bodies (MIBS)
CDK1 that are enriched in CDK1-phosphorylated p62 and K63 polyubiquitin chains

Summary

Introduction

During their progression through mitosis, cells undergo major and reversible changes in their shape and mechanics that contribute to accurate cell division. Evidence indicates that protein quality control (PQC) systems, involving molecular chaperones of the heat shock protein (HSP) family and their cochaperones, contribute to the fidelity of cell division [3,4,5,6,7,8,9,10,11] These PQC systems can assist the spatial and timely assembly–disassembly of protein complexes and resolve damages in proteins and cytoskeletal structures [12,13,14,15].

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