USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2

被引：42

作者：

Chen, Lei-lei ^{[1
]}

Smith, Matthew D. ^{[1
]}

Lv, Lei ^{[1
,6
]}

Nakagawa, Tadashi ^{[1
,7
]}

Li, Zhijun ^{[1
]}

Sun, Shao-Cong ^{[2
]}

Brown, Nicholas G. ^{[1
,3
]}

Xiong, Yue ^{[1
,4
]}

Xu, Yan-ping ^{[1
,5
]}

机构：

[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA

[3] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27515 USA

[4] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27515 USA

[5] Tongji Univ, Sch Life Sci & Technol, Shanghai Key Lab Signaling & Dis Res, Shanghai 200092, Peoples R China

[6] Fudan Univ, Dept Biochem & Mol Biol, Shanghai Med Coll, Shanghai 200032, Peoples R China

[7] Tohoku Univ, Grad Sch Med, Div Cell Proliferat, ART, Sendai, Miyagi 9808575, Japan

来源：

SCIENCE ADVANCES | 2020年 / 6卷 / 38期

关键词：

HEMATOPOIETIC STEM-CELLS; CRL4(VPRBP) E3 LIGASE; ONCOMETABOLITE; 2-HYDROXYGLUTARATE; DNA DEMETHYLATION; MUTATIONS RESULT; SELF-RENEWAL; 5-HYDROXYMETHYLCYTOSINE; 5-METHYLCYTOSINE; EXPRESSION; METHYLATION;

D O I：

10.1126/sciadv.abc9730

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

TET2 DNA dioxygenase is frequently mutated in human hematopoietic malignancies and functionally inactivated in many solid tumors through a nonmutational mechanism. We recently found that TET2 mediates the interferon-JAK-STAT pathway to stimulate chemokine expression and tumor infiltration of lymphocytes (TILs). TET2 is mono-ubiquitylated at K1299, which promotes its activity. Here, we report that USP15 is a TET2 deubiquitinase and inhibitor. USP15 catalyzes the removal of K1299-linked monoubiquitin and negatively regulates TET2 activity. Gene expression profiling demonstrates that TET2 and USP15 oppositely regulate genes involved in multiple inflammatory pathways, and TET2 is a major target of USP15 function. Deletion of Usp15 in melanoma stimulates chemokine expression and TILs in a TET2-dependent manner, leading to increased response to immunotherapy and extended life span of tumor-bearing mice. These results reveal a previously unknown regulator of TET2 activity and suggest USP15 as a potential therapeutic target for immunotherapy of solid tumors.

引用

页数：13

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