PT - JOURNAL ARTICLE AU - Ekaterina V. Vinogradova AU - Daniel C. Lazar AU - Radu M. Suciu AU - Yujia Wang AU - Giulia Bianco AU - Yu Yamashita AU - Vincent M. Crowley AU - Dave Remillard AU - Kenneth M. Lum AU - Gabriel M. Simon AU - Esther K. Kemper AU - Michael R. Lazear AU - Sifei Yin AU - Megan M. Blewett AU - Melissa M. Dix AU - Nhan Nguyen AU - Maxim N. Shokhirev AU - Emily Chin AU - Luke Lairson AU - Stefano Forli AU - John R. Teijaro AU - Benjamin F. Cravatt TI - An activity-guided map of electrophile-cysteine interactions in primary human immune cells AID - 10.1101/808113 DP - 2019 Jan 01 TA - bioRxiv PG - 808113 4099 - http://biorxiv.org/content/early/2019/10/17/808113.short 4100 - http://biorxiv.org/content/early/2019/10/17/808113.full AB - 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 3000 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 direct functional perturbation and/or ligand-induced degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells, underscoring the potential of electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.