美国斯克里普斯研究所Benjamin F. Cravatt和John R. Teijaro研究组合作取得新进展。他们绘制了原代人类T细胞中亲电半胱氨酸相互作用的活性导图。相关论文发表在2020年7月29日出版的《细胞》杂志上。

他们提出了初级人类细胞中的半胱氨酸的全图谱，这些半胱氨酸易被亲电子小分子共价修饰。在功能和结构上多样化的蛋白质上发现了3,000多种共价配体的半胱氨酸，包括许多在免疫学中起基本作用的蛋白质。

他们进一步表明，亲电子化合物可以通过涉及蛋白质直接功能性扰动和/或降解的不同机制来减弱T细胞活化。他们的发现揭示了人类T细胞中可配基半胱氨酸的丰富含量，并指出亲电小分子可作为化学探针和调节免疫过程及其相关疾病的最终疗法的沃土。

研究人员表示，源自自然或化学合成的亲电化合物对免疫细胞产生深远的影响。人们认为这些化合物通过半胱氨酸修饰来改变免疫相关蛋白的功能。然而，他们对人类免疫蛋白质组中亲电子敏感的半胱氨酸的了解仍然有限。

附：英文原文

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

Author: Ekaterina V. Vinogradova, Xiaoyu Zhang, David Remillard, Daniel C. Lazar, Radu M. Suciu, Yujia Wang, Giulia Bianco, Yu Yamashita, Vincent M. Crowley, Michael A. Schafroth, Minoru Yokoyama, David B. Konrad, Kenneth M. Lum, Gabriel M. Simon, Esther K. Kemper, Michael R. Lazear, Sifei Yin, Megan M. Blewett, Melissa M. Dix, Nhan Nguyen, Maxim N. Shokhirev, Emily N. Chin, Luke L. Lairson, Bruno Melillo, Stuart L. Schreiber, Stefano Forli, John R. Teijaro, Benjamin F. Cravatt

Issue&Volume: 2020-07-29

Abstract: Electrophilic compounds originating from nature or chemical synthesis have profoundeffects on immune cells. These compounds are thought to act by cysteine modificationto alter the functions of immune-relevant proteins; however, our understanding ofelectrophile-sensitive cysteines in the human immune proteome remains limited. Here,we present a global map of cysteines in primary human T cells that are susceptibleto covalent modification by electrophilic small molecules. More than 3,000 covalentlyliganded cysteines were found on functionally and structurally diverse proteins, includingmany that play fundamental roles in immunology. We further show that electrophiliccompounds can impair T cell activation by distinct mechanisms involving the directfunctional perturbation and/or degradation of proteins. Our findings reveal a richcontent of ligandable cysteines in human T cells and point to electrophilic smallmolecules as a fertile source for chemical probes and ultimately therapeutics thatmodulate immunological processes and their associated disorders.

DOI: 10.1016/j.cell.2020.07.001

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30823-0