@article{02099c3e5dbe40458aef50a39da58c9d,
title = "An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells",
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",
author = "Vinogradova, {Ekaterina V.} and Xiaoyu Zhang and David Remillard and Lazar, {Daniel C.} and Suciu, {Radu M.} and Yujia Wang and Giulia Bianco and Yu Yamashita and Crowley, {Vincent M.} and Schafroth, {Michael A.} and Minoru Yokoyama and Konrad, {David B.} and Lum, {Kenneth M.} and Simon, {Gabriel M.} and Kemper, {Esther K.} and Lazear, {Michael R.} and Sifei Yin and Blewett, {Megan M.} and Dix, {Melissa M.} and Nhan Nguyen and Shokhirev, {Maxim N.} and Chin, {Emily N.} and Lairson, {Luke L.} and Bruno Melillo and Schreiber, {Stuart L.} and Stefano Forli and Teijaro, {John R.} and Cravatt, {Benjamin F.}",
note = "Funding Information: We thank D. Tallman for technical assistance, B. Lu for help with Table S4, and M. Niphakis for helpful discussions. This work was supported by NIH ( CA231991 to B.F.C.), NIH-NCI ( K99CA248715 to X.Z., CA212467 to V.M.C., CA211526 to M.M.D., and GM069832 to S.F.), a Clinical Translational Science Award ( UL1 TR001114 ), Damon Runyon Cancer Research Foundation ( DRG-2341-18 to X.Z.), the Life Sciences Research Foundation (to E.V.V.), and Vividion Therapeutics . M.N.S. was supported by funding from NIH-NCI CCSG ( P30 014195 and R01 GM102491-07 ), and the Helmsley Trust . D.B.K. received funding from the European Union{\textquoteright}s Framework Programme for Research and Innovation Horizon 2020 ( 2014-2020 ). Funding Information: We thank D. Tallman for technical assistance, B. Lu for help with Table S4, and M. Niphakis for helpful discussions. This work was supported by NIH (CA231991 to B.F.C.), NIH-NCI (K99CA248715 to X.Z. CA212467 to V.M.C. CA211526 to M.M.D. and GM069832 to S.F.), a Clinical Translational Science Award (UL1 TR001114), Damon Runyon Cancer Research Foundation (DRG-2341-18 to X.Z.), the Life Sciences Research Foundation (to E.V.V.), and Vividion Therapeutics. M.N.S. was supported by funding from NIH-NCI CCSG (P30 014195 and R01 GM102491-07), and the Helmsley Trust. D.B.K. received funding from the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014-2020). Conceptualization, E.V.V. J.R.T. and B.F.C.; Methodology, E.V.V. D.C.L. M.M.B. J.R.T. G.B. B.M. S.L.S. and B.F.C.; Formal Analysis, E.V.V. R.M.S. Y.W. and B.F.C.; Investigation, E.V.V. X.Z. D.R. D.C.L. Y.Y. V.M.C. M.A.S. M.Y. D.B.K. E.K.K. M.R.L. S.Y. M.M.D. N.N. E.N.C. and L.L.L.; Resources, E.V.V. G.M.S. R.M.S. and K.M.L.; Data Curation, E.V.V. R.M.S. Y.W. M.N.S. S.F. and B.F.C.; Writing ? Original Draft, E.V.V.; Writing ? Review & Editing, E.V.V. and B.F.C.; Visualization, E.V.V. G.B. R.M.S. and B.F.C.; Supervision, E.V.V. J.R.T. and B.F.C. B.F.C. is a founder and scientific advisor to Vividion Therapeutics. B.F.C. V.M.C. B.M. D.R. M.A.S. E.V.V. X.Z. and M.Y. are co-inventors on a patent application related to this work. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = aug,
day = "20",
doi = "10.1016/j.cell.2020.07.001",
language = "English (US)",
volume = "182",
pages = "1009--1026.e29",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}