Nature Communications (Jun 2023)

Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation

  • Anna Rodina,
  • Chao Xu,
  • Chander S. Digwal,
  • Suhasini Joshi,
  • Yogita Patel,
  • Anand R. Santhaseela,
  • Sadik Bay,
  • Swathi Merugu,
  • Aftab Alam,
  • Pengrong Yan,
  • Chenghua Yang,
  • Tanaya Roychowdhury,
  • Palak Panchal,
  • Liza Shrestha,
  • Yanlong Kang,
  • Sahil Sharma,
  • Justina Almodovar,
  • Adriana Corben,
  • Mary L. Alpaugh,
  • Shanu Modi,
  • Monica L. Guzman,
  • Teng Fei,
  • Tony Taldone,
  • Stephen D. Ginsberg,
  • Hediye Erdjument-Bromage,
  • Thomas A. Neubert,
  • Katia Manova-Todorova,
  • Meng-Fu Bryan Tsou,
  • Jason C. Young,
  • Tai Wang,
  • Gabriela Chiosis

DOI
https://doi.org/10.1038/s41467-023-39241-7
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 26

Abstract

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Abstract Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based ‘omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.