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, Q., Jin, J., Hu, H., Li, H.S., Romano, S., Xiao, Y., Nakaya, M., Zhou, X., Cheng, X., Yang, P., Lozano, G., Zhu, C., Watowich, S.S., Ullrich, S.E., Sun, S.. - 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
