A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol

摘要

很多研究报告都显示了白藜芦醇(葡萄皮和红葡萄酒的一个天然成分)对健康的好处。它被认为通过启动能诱导生存基因的一个应激反应来延长寿命和防止发生各种疾病。在这篇论文中,Mathew Sajish和Paul Schimmel发表了白藜芦醇与人类"tyrosyl tRNA synthetase"(TyrRS,在压力条件下向细胞核中转移的一种酶)的活性点相结合的一个分辨率为2.1A的共晶体结构。他们看到，白藜芦醇抑制催化活rn性，将TyrAS向一个核功能重新引导，刺激PARP-1 (poly (ADP-ribose) polymerase 1)发生依赖于NAD~+的"auto-poly-ADP-ribosylation"反应，导致关键应激信号传导通道的激发。这项工作提出了白藜芦醇除了与组蛋白脱乙酰酶SIRT1结合和激发它之外的另一个作用机制。%Resveratrol is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a stress response that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions, we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 A co-crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD~+-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS-PARP1-NAD~+ collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites, here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD~+-dependent dimension to the physiological mechanism of resveratrol.