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

Nat Commun. 2024 Oct 16;15(1):8912. doi: 10.1038/s41467-024-53178-5.

Tanaya Roychowdhury ^# ¹, Seth W McNutt ^# ², Chiranjeevi Pasala ^# ¹, Hieu T Nguyen ², Daniel T Thornton ², Sahil Sharma ¹, Luke Botticelli ², Chander S Digwal ¹, Suhasini Joshi ¹, Nan Yang ², Palak Panchal ¹, Souparna Chakrabarty ¹, Sadik Bay ¹, Vladimir Markov ³, Charlene Kwong ³, Jeanine Lisanti ³, Sun Young Chung ¹, Stephen D Ginsberg ⁴ ⁵, Pengrong Yan ¹, Elisa De Stanchina ³, Adriana Corben ⁶ ⁷, Shanu Modi ⁸, Mary L Alpaugh ¹ ⁹, Giorgio Colombo ¹⁰, Hediye Erdjument-Bromage ¹¹, Thomas A Neubert ¹¹, Robert J Chalkley ¹², Peter R Baker ¹², Alma L Burlingame ¹², Anna Rodina ¹, Gabriela Chiosis ¹³ ¹⁴, Feixia Chu ¹⁵ ¹⁶

Affiliations

1 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2 Department of Molecular, Cellular & Biomedical Sciences, University of New Hampshire, Durham, NH, USA.
3 Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4 Departments of Psychiatry, Neuroscience & Physiology & the NYU Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA.
5 Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA.
6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7 Maimonides Medical Center, Brooklyn, NY, USA.
8 Department of Medicine, Division of Solid Tumors, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9 Rowan University, Glassboro, NJ, USA.
10 Department of Chemistry, University of Pavia, Pavia, Italy.
11 Department of Neuroscience and Physiology and Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA.
12 Mass Spectrometry Facility, University of California, San Francisco, CA, USA.
13 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chiosisg@mskcc.org.
14 Department of Medicine, Division of Solid Tumors, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chiosisg@mskcc.org.
15 Department of Molecular, Cellular & Biomedical Sciences, University of New Hampshire, Durham, NH, USA. feixia.chu@unh.edu.
16 Hubbard Center for Genome Studies, University of New Hampshire, Durham, NH, USA. feixia.chu@unh.edu.
# Contributed equally.

PMID: 39414766 DOI: 10.1038/s41467-024-53178-5

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.

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HY-50855

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Casein Kinase; Autophagy

Cancer

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