USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2
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 lymphoc...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500937/ https://www.ncbi.nlm.nih.gov/pubmed/32948596 http://dx.doi.org/10.1126/sciadv.abc9730 |
_version_ | 1783583953804853248 |
---|---|
author | Chen, Lei-lei Smith, Matthew D. Lv, Lei Nakagawa, Tadashi Li, Zhijun Sun, Shao-Cong Brown, Nicholas G. Xiong, Yue Xu, Yan-ping |
author_facet | Chen, Lei-lei Smith, Matthew D. Lv, Lei Nakagawa, Tadashi Li, Zhijun Sun, Shao-Cong Brown, Nicholas G. Xiong, Yue Xu, Yan-ping |
author_sort | Chen, Lei-lei |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7500937 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-75009372020-09-24 USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2 Chen, Lei-lei Smith, Matthew D. Lv, Lei Nakagawa, Tadashi Li, Zhijun Sun, Shao-Cong Brown, Nicholas G. Xiong, Yue Xu, Yan-ping Sci Adv Research Articles 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. American Association for the Advancement of Science 2020-09-18 /pmc/articles/PMC7500937/ /pubmed/32948596 http://dx.doi.org/10.1126/sciadv.abc9730 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Chen, Lei-lei Smith, Matthew D. Lv, Lei Nakagawa, Tadashi Li, Zhijun Sun, Shao-Cong Brown, Nicholas G. Xiong, Yue Xu, Yan-ping USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2 |
title | USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2 |
title_full | USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2 |
title_fullStr | USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2 |
title_full_unstemmed | USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2 |
title_short | USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2 |
title_sort | usp15 suppresses tumor immunity via deubiquitylation and inactivation of tet2 |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500937/ https://www.ncbi.nlm.nih.gov/pubmed/32948596 http://dx.doi.org/10.1126/sciadv.abc9730 |
work_keys_str_mv | AT chenleilei usp15suppressestumorimmunityviadeubiquitylationandinactivationoftet2 AT smithmatthewd usp15suppressestumorimmunityviadeubiquitylationandinactivationoftet2 AT lvlei usp15suppressestumorimmunityviadeubiquitylationandinactivationoftet2 AT nakagawatadashi usp15suppressestumorimmunityviadeubiquitylationandinactivationoftet2 AT lizhijun usp15suppressestumorimmunityviadeubiquitylationandinactivationoftet2 AT sunshaocong usp15suppressestumorimmunityviadeubiquitylationandinactivationoftet2 AT brownnicholasg usp15suppressestumorimmunityviadeubiquitylationandinactivationoftet2 AT xiongyue usp15suppressestumorimmunityviadeubiquitylationandinactivationoftet2 AT xuyanping usp15suppressestumorimmunityviadeubiquitylationandinactivationoftet2 |