Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90's interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

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Publication Details

Journal
Nature Communications
Published
2024-10-16
DOI
https://doi.org/10.1038/s41467-024-53178-5
Citations
22
Primary Topic
Heat shock proteins research
Type
article
Field-Weighted Citation Impact
5.14

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article

Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation

Adriana Corben, Elisa de Stanchina, Sun Young Chung, Shanu Modi et al.
22 citations
Nature Communications
Heat shock proteins research
5.14
article

Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation

Adriana Corben, Elisa de Stanchina, Sun Young Chung, Shanu Modi, Robert J. Chalkley, Chiranjeevi Pasala, Gabriela Chiosis, Giorgio Colombo, Sahil Sharma, Peter R. Baker, Chander Singh Digwal, Stephen D. Ginsberg, Seth McNutt, Hieu Thi Nguyen, Souparna Chakrabarty, Thomas A. Neubert, Alma L. Burlingame, Pengrong Yan, Anna Rodina, Suhasini Joshi, Palak Panchal, Daniel T. Thornton, Mary L. Alpaugh, Hediye Erdjument‐Bromage, Feixia Chu, Charlene Kwong, Tanaya Roychowdhury, Sadık Bay, Jeanine Lisanti, Luke Botticelli, Nan Yang, Vladimir Markov
article en
22 citations

Abstract

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90's interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

Nature CommunicationsVol. 15(1)
Nathan Kline Institute for Psychiatric Research (US), Maimonides Medical Center (US), Memorial Sloan Kettering Cancer Center (US), University of New Hampshire (US), University of California, San Francisco (US), Neurosciences Institute (US), University of Pavia (IT), Rowan University (US)
National Science Foundation, BrightFocus Foundation, Memorial Sloan-Kettering Cancer Center, Associazione Italiana per la Ricerca sul Cancro, National Institutes of Health, National Institute on Aging, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 4%
Heat shock proteins research
5.14
DOIOpen Access PDFOpenAlex
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