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

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

doi:10.1038/s41467-024-53178-5

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

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

Biological Sciences

Rowan University

Research output: Contribution to journal › Article › peer-review

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.

Original language	American English
Article number	8912
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-53178-5
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-024-53178-5

Cite this

Roychowdhury, T., McNutt, S. W., Pasala, C., Nguyen, H. T., Thornton, D. T., Sharma, S., Botticelli, L., Digwal, C. S., Joshi, S., Yang, N., Panchal, P., Chakrabarty, S., Bay, S., Markov, V., Kwong, C., Lisanti, J., Chung, S. Y., Ginsberg, S. D., Yan, P., ... Chu, F. (2024). Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation. Nature communications, 15(1), Article 8912. https://doi.org/10.1038/s41467-024-53178-5

@article{38fc054fc66a432280018c40a99aad03,

title = "Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation",

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{\textquoteright}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.",

author = "Tanaya Roychowdhury and McNutt, {Seth W.} and Chiranjeevi Pasala and Nguyen, {Hieu T.} and Thornton, {Daniel T.} and Sahil Sharma and Luke Botticelli and Digwal, {Chander S.} and Suhasini Joshi and Nan Yang and Palak Panchal and Souparna Chakrabarty and Sadik Bay and Vladimir Markov and Charlene Kwong and Jeanine Lisanti and Chung, {Sun Young} and Ginsberg, {Stephen D.} and Pengrong Yan and {De Stanchina}, Elisa and Adriana Corben and Shanu Modi and Alpaugh, {Mary L.} and Giorgio Colombo and Hediye Erdjument-Bromage and Neubert, {Thomas A.} and Chalkley, {Robert J.} and Baker, {Peter R.} and Burlingame, {Alma L.} and Anna Rodina and Gabriela Chiosis and Feixia Chu",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-53178-5",

language = "American English",

volume = "15",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Roychowdhury, T, McNutt, SW, Pasala, C, Nguyen, HT, Thornton, DT, Sharma, S, Botticelli, L, Digwal, CS, Joshi, S, Yang, N, Panchal, P, Chakrabarty, S, Bay, S, Markov, V, Kwong, C, Lisanti, J, Chung, SY, Ginsberg, SD, Yan, P, De Stanchina, E, Corben, A, Modi, S, Alpaugh, ML, Colombo, G, Erdjument-Bromage, H, Neubert, TA, Chalkley, RJ, Baker, PR, Burlingame, AL, Rodina, A, Chiosis, G & Chu, F 2024, 'Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation', Nature communications, vol. 15, no. 1, 8912. https://doi.org/10.1038/s41467-024-53178-5

TY - JOUR

T1 - Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation

AU - Roychowdhury, Tanaya

AU - McNutt, Seth W.

AU - Pasala, Chiranjeevi

AU - Nguyen, Hieu T.

AU - Thornton, Daniel T.

AU - Sharma, Sahil

AU - Botticelli, Luke

AU - Digwal, Chander S.

AU - Joshi, Suhasini

AU - Yang, Nan

AU - Panchal, Palak

AU - Chakrabarty, Souparna

AU - Bay, Sadik

AU - Markov, Vladimir

AU - Kwong, Charlene

AU - Lisanti, Jeanine

AU - Chung, Sun Young

AU - Ginsberg, Stephen D.

AU - Yan, Pengrong

AU - De Stanchina, Elisa

AU - Corben, Adriana

AU - Modi, Shanu

AU - Alpaugh, Mary L.

AU - Colombo, Giorgio

AU - Erdjument-Bromage, Hediye

AU - Neubert, Thomas A.

AU - Chalkley, Robert J.

AU - Baker, Peter R.

AU - Burlingame, Alma L.

AU - Rodina, Anna

AU - Chiosis, Gabriela

AU - Chu, Feixia

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85206591359&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85206591359&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-53178-5

DO - 10.1038/s41467-024-53178-5

M3 - Article

C2 - 39414766

SN - 2041-1723

VL - 15

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 8912

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this