USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses

作者：Zou Qiang; Jin Jin; Hu Hongbo; Li Haiyan S; Romano Simona; Xiao Yichuan; Nakaya Mako; Zhou Xiaofei; Cheng Xuhong; Yang Peirong; Lozano Guillermina; Zhu Chengming; Watowich Stephanie S; Ullrich Stephen E; Sun Shao Cong^*

来源：Nature Immunology, 2014, 15(6): 562-570.

DOI：10.1038/ni.2885

Deubiquitinases (DUBs) are a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.

• 出版日期2014-6