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The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation

Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Usi...

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Autores principales: Boyd, Rowan A., Majumder, Saurav, Stiban, Johnny, Mavodza, Grace, Straus, Alexandra J., Kempelingaiah, Sachin K., Reddy, Varun, Hannun, Yusuf A., Obeid, Lina M., Senkal, Can E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10591768/
https://www.ncbi.nlm.nih.gov/pubmed/37689067
http://dx.doi.org/10.1016/j.celrep.2023.113081
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author Boyd, Rowan A.
Majumder, Saurav
Stiban, Johnny
Mavodza, Grace
Straus, Alexandra J.
Kempelingaiah, Sachin K.
Reddy, Varun
Hannun, Yusuf A.
Obeid, Lina M.
Senkal, Can E.
author_facet Boyd, Rowan A.
Majumder, Saurav
Stiban, Johnny
Mavodza, Grace
Straus, Alexandra J.
Kempelingaiah, Sachin K.
Reddy, Varun
Hannun, Yusuf A.
Obeid, Lina M.
Senkal, Can E.
author_sort Boyd, Rowan A.
collection PubMed
description Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.
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spelling pubmed-105917682023-10-23 The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation Boyd, Rowan A. Majumder, Saurav Stiban, Johnny Mavodza, Grace Straus, Alexandra J. Kempelingaiah, Sachin K. Reddy, Varun Hannun, Yusuf A. Obeid, Lina M. Senkal, Can E. Cell Rep Article Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27. 2023-09-26 2023-09-08 /pmc/articles/PMC10591768/ /pubmed/37689067 http://dx.doi.org/10.1016/j.celrep.2023.113081 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Boyd, Rowan A.
Majumder, Saurav
Stiban, Johnny
Mavodza, Grace
Straus, Alexandra J.
Kempelingaiah, Sachin K.
Reddy, Varun
Hannun, Yusuf A.
Obeid, Lina M.
Senkal, Can E.
The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation
title The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation
title_full The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation
title_fullStr The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation
title_full_unstemmed The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation
title_short The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation
title_sort heat shock protein hsp27 controls mitochondrial function by modulating ceramide generation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10591768/
https://www.ncbi.nlm.nih.gov/pubmed/37689067
http://dx.doi.org/10.1016/j.celrep.2023.113081
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