Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin
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 s...
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| Format: | Article |
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/1/142 |
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| author | Carole Luthold Alice-Anaïs Varlet Herman Lambert François Bordeleau Josée N. Lavoie |
| author_facet | Carole Luthold Alice-Anaïs Varlet Herman Lambert François Bordeleau Josée N. Lavoie |
| author_sort | Carole Luthold |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T13:46:35Z |
| format | Article |
| id | doaj.art-82fb81a571ee4d889a67b91ce1fb6dda |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:46:35Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-82fb81a571ee4d889a67b91ce1fb6dda2023-11-21T02:33:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-0122114210.3390/ijms22010142Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate CortactinCarole Luthold0Alice-Anaïs Varlet1Herman Lambert2François Bordeleau3Josée N. Lavoie4Centre de Recherche sur le Cancer, Université Laval, Québec, QC G1R 3S3, CanadaCentre de Recherche sur le Cancer, Université Laval, Québec, QC G1R 3S3, CanadaCentre de Recherche sur le Cancer, Université Laval, Québec, QC G1R 3S3, CanadaCentre de Recherche sur le Cancer, Université Laval, Québec, QC G1R 3S3, CanadaCentre de Recherche sur le Cancer, Université Laval, Québec, QC G1R 3S3, CanadaThe 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.https://www.mdpi.com/1422-0067/22/1/142BAG3 1HSPB8 2p62/SQSTM1 3HDAC6 4Arp2/3 5cortactin 6 |
| spellingShingle | Carole Luthold Alice-Anaïs Varlet Herman Lambert François Bordeleau Josée N. Lavoie Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin International Journal of Molecular Sciences BAG3 1 HSPB8 2 p62/SQSTM1 3 HDAC6 4 Arp2/3 5 cortactin 6 |
| title | Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin |
| title_full | Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin |
| title_fullStr | Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin |
| title_full_unstemmed | Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin |
| title_short | Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin |
| title_sort | chaperone assisted mitotic actin remodeling by bag3 and hspb8 involves the deacetylase hdac6 and its substrate cortactin |
| topic | BAG3 1 HSPB8 2 p62/SQSTM1 3 HDAC6 4 Arp2/3 5 cortactin 6 |
| url | https://www.mdpi.com/1422-0067/22/1/142 |
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