USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses.
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.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Qiang
Q
Zou
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Jin
J
Jin
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Hongbo
H
Hu
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Haiyan S
HS
Li
1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [2] Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy.
Simona
S
Romano
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Yichuan
Y
Xiao
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Mako
M
Nakaya
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Xiaofei
X
Zhou
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Xuhong
X
Cheng
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Peirong
P
Yang
1] Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
Guillermina
G
Lozano
1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
Chengming
C
Zhu
1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
Stephanie S
SS
Watowich
1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
Stephen E
SE
Ullrich
1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
Shao-Cong
SC
Sun
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival; D045325:HCT116 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D019139:Tumor Escape; D016159:Tumor Suppressor Protein p53 / Q000276:immunology; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000276:immunology*; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology
D007976:Leupeptins; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde