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  3. An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells

An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells

  • Cell. 2020 Aug 20;182(4):1009-1026.e29. doi: 10.1016/j.cell.2020.07.001.
Ekaterina V Vinogradova 1,  Xiaoyu Zhang 2,  David Remillard 2,  Daniel C Lazar 3,  Radu M Suciu 2,  Yujia Wang 2,  Giulia Bianco 4,  Yu Yamashita 5,  Vincent M Crowley 2,  Michael A Schafroth 2,  Minoru Yokoyama 2,  David B Konrad 2,  Kenneth M Lum 2,  Gabriel M Simon 6,  Esther K Kemper 2,  Michael R Lazear 2,  Sifei Yin 2,  Megan M Blewett 2,  Melissa M Dix 2,  Nhan Nguyen 3,  Maxim N Shokhirev 7,  Emily N Chin 2,  Luke L Lairson 2,  Bruno Melillo 8,  Stuart L Schreiber 9,  Stefano Forli 4,  John R Teijaro 10,  Benjamin F Cravatt 11
Affiliations

Affiliations

  • 1 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 2 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 3 Department of Immunology and Infectious Disease, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 4 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 5 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA; Medicinal Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kawauchi-cho, Tokushima 771-0192, Japan.
  • 6 Vividion Therapeutics, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA.
  • 7 Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • 8 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA 02138, USA.
  • 9 Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA 02138, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • 10 Department of Immunology and Infectious Disease, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 11 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID: 32730809 DOI: 10.1016/j.cell.2020.07.001
Abstract

Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3,000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving the direct functional perturbation and/or degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.

Keywords

BIRC3; ITK; T cells; activity-based protein profiling; chemical proteomics; covalent; cysteine; electrophiles; human; protein degradation.

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