Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/ijms22010142
Keywords
BAG3 1; HSPB8 2; p62/SQSTM1 3; HDAC64; Arp2/3 5; cortactin 6; mitosis 7; actin cloud 8; actin remodeling 9
Funding
- Canadian Institutes of Health Research [7088]
- Foundation of the Centre Hospitalier Universitaire (CHU) de Quebec [82536]
- National Science and Engineering Council of Canada (NSERC) [RGPIN-2018-06214]
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The study reveals that during mitosis, BAG3 interacts with HSPB8, p62/SQSTM1, and HDAC6 to regulate cell rounding, cortex stability, and spindle orientation. Depletion of BAG3 affects subcortical actin cloud dynamics and impairs spindle positioning. These effects can be corrected by drugs inhibiting the Arp2/3 complex or HDAC6 activity, indicating a role for BAG3 in tuning branched actin network assembly.
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.
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