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.

USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses / 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. - In: NATURE IMMUNOLOGY. - ISSN 1529-2908. - 15:6(2014), pp. 562-570. [10.1038/ni.2885]

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

Romano, Simona;
2014

Abstract

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.
2014
USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses / 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. - In: NATURE IMMUNOLOGY. - ISSN 1529-2908. - 15:6(2014), pp. 562-570. [10.1038/ni.2885]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/738107
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