Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin.

Carole Luthold,François Bordeleau,Josée N Lavoie,Herman Lambert,Alice-Anaïs Varlet

doi:10.3390/ijms22010142

Carole Luthold, François Bordeleau + Show 3 more

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https://doi.org/10.3390/ijms22010142

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Abstract

The fidelity of actin dynamics relies on protein quality control, but the underlying molecular mechanisms are poorly defined. During mitosis, the cochaperone BCL2-associated athanogene 3 (BAG3) modulates cell rounding, cortex stability, spindle orientation, and chromosome segregation. Mitotic BAG3 shows enhanced interactions with its preferred chaperone partner HSPB8, the autophagic adaptor p62/SQSTM1, and HDAC6, a deacetylase with cytoskeletal substrates. Here, we show that depletion of BAG3, HSPB8, or p62/SQSTM1 can recapitulate the same inhibition of mitotic cell rounding. Moreover, depletion of either of these proteins also interfered with the dynamic of the subcortical actin cloud that contributes to spindle positioning. These phenotypes were corrected by drugs that limit the Arp2/3 complex or HDAC6 activity, arguing for a role for BAG3 in tuning branched actin network assembly. Mechanistically, we found that cortactin acetylation/deacetylation is mitotically regulated and is correlated with a reduced association of cortactin with HDAC6 in situ. Remarkably, BAG3 depletion hindered the mitotic decrease in cortactin–HDAC6 association. Furthermore, expression of an acetyl-mimic cortactin mutant in BAG3-depleted cells normalized mitotic cell rounding and the subcortical actin cloud organization. Together, these results reinforce a BAG3′s function for accurate mitotic actin remodeling, via tuning cortactin and HDAC6 spatial dynamics.

Highlights

Key biological processes rely on a strict control of cell shape change through remodeling of the actin cortex, including cell migration, differentiation, and mitotic cell division [1,2]
We show that the depletion of BCL2-associated athanogene 3 (BAG3) and its mitotic partners, HSPB8 and p62/SQSTM1, recapitulated the same mitotic cell rounding defects that were normalized by the downregulation of
We have previously shown that BAG3 forms a mitotic complex with HSPB8, p62/SQSTM1, and histone deacetylase 6 (HDAC6) [16]

Summary

Introduction

Key biological processes rely on a strict control of cell shape change through remodeling of the actin cortex, including cell migration, differentiation, and mitotic cell division [1,2]. Rapid disassembly of the interphase actin network and focal adhesions at mitotic entry enables the formation of a rigid actomyosin cortex that drives mitotic cell rounding. This process is facilitated by the targeted degradation of cortical proteins [6]. Mitotic cell rounding crucially relies on a spatial control of distinct actin nucleation activities to assemble the contractile actin cortex.

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