Unknown

Dataset Information

0

USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2.


ABSTRACT: 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 monoubiquitylated 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.

SUBMITTER: Chen LL 

PROVIDER: S-EPMC7500937 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications

USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2.

Chen Lei-Lei LL   Smith Matthew D MD   Lv Lei L   Nakagawa Tadashi T   Li Zhijun Z   Sun Shao-Cong SC   Brown Nicholas G NG   Xiong Yue Y   Xu Yan-Ping YP  

Science advances 20200918 38


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 monoubiquitylated at K1299, which promotes its activity. Here, we report that USP15 is a TET2 deubiquitinase and inhibitor. USP15 catalyzes the removal of K1299-linked monoubiquit  ...[more]

Similar Datasets

| S-EPMC9638925 | biostudies-literature
| S-EPMC4042855 | biostudies-other
| S-EPMC8137576 | biostudies-literature
| S-EPMC6763236 | biostudies-literature
| S-EPMC2631340 | biostudies-literature
| S-EPMC7012179 | biostudies-literature
| S-EPMC7929805 | biostudies-literature
2023-03-21 | GSE203466 | GEO
| PRJNA840921 | ENA
| S-EPMC5746398 | biostudies-literature