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

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

doi:10.1038/ni.2885

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

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

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184 Scopus citations

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.

Original language	English (US)
Pages (from-to)	562-570
Number of pages	9
Journal	Nature Immunology
Volume	15
Issue number	6
DOIs	https://doi.org/10.1038/ni.2885
State	Published - Jun 2014

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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@article{1aa747498ea4482bbce80db907139067,

title = "USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses",

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.",

author = "Qiang Zou and Jin Jin and Hongbo Hu and Li, {Haiyan S.} and Simona Romano and Yichuan Xiao and Mako Nakaya and Xiaofei Zhou and Xuhong Cheng and Peirong Yang and Guillermina Lozano and Chengming Zhu and Watowich, {Stephanie S.} and Ullrich, {Stephen E.} and Sun, {Shao Cong}",

note = "Funding Information: We thank W. Gu for expression vectors, B. Vogelstein for HCT116 derivative cell lines, S. Hao for recombinant L. monocytogenesis, Q. Yi for B16 cell line, L.A. Donehower for Trp53−/− mice, and the personnel from the US National Institutes of Health or National Cancer Insitute–supported resources (flow cytometry, DNA analysis and animal facilities) under award number P30CA016672 at The MD Anderson Cancer Center. This study was supported by grants from US National Institutes of Health (AI057555, AI064639, GM84459 and AI104519 to S.-C.S. and AI098099 to S.S.W.) and partially supported by a Sister Institution Network Fund and a seed fund from the Center for Inflammation and Cancer at the MD Anderson Cancer Center.",

year = "2014",

month = jun,

doi = "10.1038/ni.2885",

language = "English (US)",

volume = "15",

pages = "562--570",

journal = "Nature Immunology",

issn = "1529-2908",

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T1 - USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses

AU - Zou, Qiang

AU - Jin, Jin

AU - Hu, Hongbo

AU - Li, Haiyan S.

AU - Romano, Simona

AU - Xiao, Yichuan

AU - Nakaya, Mako

AU - Zhou, Xiaofei

AU - Cheng, Xuhong

AU - Yang, Peirong

AU - Lozano, Guillermina

AU - Zhu, Chengming

AU - Watowich, Stephanie S.

AU - Ullrich, Stephen E.

AU - Sun, Shao Cong

N1 - Funding Information: We thank W. Gu for expression vectors, B. Vogelstein for HCT116 derivative cell lines, S. Hao for recombinant L. monocytogenesis, Q. Yi for B16 cell line, L.A. Donehower for Trp53−/− mice, and the personnel from the US National Institutes of Health or National Cancer Insitute–supported resources (flow cytometry, DNA analysis and animal facilities) under award number P30CA016672 at The MD Anderson Cancer Center. This study was supported by grants from US National Institutes of Health (AI057555, AI064639, GM84459 and AI104519 to S.-C.S. and AI098099 to S.S.W.) and partially supported by a Sister Institution Network Fund and a seed fund from the Center for Inflammation and Cancer at the MD Anderson Cancer Center.

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

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

Abstract

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