USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2.
USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2.
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DOI：
10.1126/sciadv.abc9730
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发表时间：
2020-09
期刊：
影响因子：
13.6
通讯作者：
Xu YP
中科院分区：
文献类型：
--
作者：
Chen LL;Smith MD;Lv L;Nakagawa T;Li Z;Sun SC;Brown NG;Xiong Y;Xu YP
USP 15去泛素化酶通过灭活TET 2抑制肿瘤免疫，是一个潜在的免疫治疗靶点。TET 2 DNA双加氧酶在人类造血系统恶性肿瘤中经常发生突变，并通过非突变机制在许多实体瘤中功能失活。我们最近发现TET 2介导干扰素-JAK-STAT途径以刺激趋化因子表达和淋巴细胞（TIL）的肿瘤浸润。TET 2在K1299处被单泛素化，这促进了其活性。在这里，我们报告USP 15是TET 2去泛素化酶和抑制剂。USP 15催化K1299连接的monoubiquitin的去除，并负调节TET 2活性。基因表达谱分析表明，TET 2和USP 15相反地调节参与多种炎症途径的基因，TET 2是USP 15功能的主要靶标。黑色素瘤中Usp 15的缺失以TET 2依赖性方式刺激趋化因子表达和TIL，导致对免疫治疗的反应增加和荷瘤小鼠的寿命延长。这些结果揭示了一种以前未知的TET 2活性调节剂，并表明USP 15是实体瘤免疫治疗的潜在治疗靶点。
USP15 deubiquitinase inactivates TET2 to suppress tumor immunity and is a potential therapeutic target of immunotherapy. 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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DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
21.3
作者：
Inui, Masafumi;Manfrin, Andrea;Piccolo, Stefano
通讯作者：
Piccolo, Stefano
影响因子：
50.3
作者：
Moran-Crusio K;Reavie L;Shih A;Abdel-Wahab O;Ndiaye-Lobry D;Lobry C;Figueroa ME;Vasanthakumar A;Patel J;Zhao X;Perna F;Pandey S;Madzo J;Song C;Dai Q;He C;Ibrahim S;Beran M;Zavadil J;Nimer SD;Melnick A;Godley LA;Aifantis I;Levine RL
通讯作者：
Levine RL
影响因子：
64.8
作者：
Agathocleous M;Meacham CE;Burgess RJ;Piskounova E;Zhao Z;Crane GM;Cowin BL;Bruner E;Murphy MM;Chen W;Spangrude GJ;Hu Z;DeBerardinis RJ;Morrison SJ
通讯作者：
Morrison SJ