Reiley William, Zhang Minying, Wu Xuefeng, Granger Erica, Sun Shao-Cong
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033, USA.
Mol Cell Biol. 2005 May;25(10):3886-95. doi: 10.1128/MCB.25.10.3886-3895.2005.
Tumor suppressor CYLD is a deubiquitinating enzyme (DUB) that inhibits the ubiquitination of key signaling molecules, including tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2). However, how the function of CYLD is regulated remains unknown. Here we provide evidence that inducible phosphorylation of CYLD is an important mechanism of its regulation. Under normal conditions, CYLD dominantly suppresses the ubiquitination of TRAF2. In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits. These findings suggest that CYLD serves as a novel target of IKK and that the site-specific phosphorylation of CYLD regulates its signaling function.
肿瘤抑制因子CYLD是一种去泛素化酶（DUB），可抑制关键信号分子的泛素化，包括肿瘤坏死因子（TNF）受体相关因子2（TRAF2）。然而，CYLD的功能是如何被调控的仍不清楚。在此我们提供证据表明，CYLD的诱导性磷酸化是其调控的重要机制。在正常条件下，CYLD主要抑制TRAF2的泛素化。响应细胞刺激时，CYLD会经历快速且短暂的磷酸化，这是信号诱导的TRAF2泛素化和下游信号事件激活所必需的。有趣的是，CYLD的磷酸化需要IkappaB激酶γ（IKKγ），并且可由IKK催化亚基诱导。这些发现表明CYLD是IKK的一个新靶点，并且CYLD的位点特异性磷酸化调节其信号功能。
