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. Epub 2020 Jul 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemistry
  • Acetamides / pharmacology
  • Acrylamides / chemistry
  • Acrylamides / pharmacology
  • Cells, Cultured
  • Cysteine / metabolism*
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Ligands*
  • Lymphocyte Activation / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Proteolysis / drug effects
  • Proteome / chemistry
  • Proteome / metabolism
  • Stereoisomerism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Ubiquitin-Protein Ligases / metabolism


  • Acetamides
  • Acrylamides
  • Inhibitor of Apoptosis Proteins
  • Ligands
  • Proteome
  • chloroacetamide
  • BIRC2 protein, human
  • Ubiquitin-Protein Ligases
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase
  • Cysteine