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...

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Autores principales: Chen, Lei-lei, Smith, Matthew D., Lv, Lei, Nakagawa, Tadashi, Li, Zhijun, Sun, Shao-Cong, Brown, Nicholas G., Xiong, Yue, Xu, Yan-ping
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
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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.
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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
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