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MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation

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收录情况： ◇ SCIE

作者：
Wang Yuan[1] * ; Jia Zhenchang[1] ; Liang Chenxi[1] ; He Yunfei[1] ; Cong Min[1] ; Wu Qiuyao[1] ; Tian Pu[1] ; He Dasa[1] ; Miao Xiang[1] ; Sun Beibei[2] ; Yin Yue[3] ; Peng Chao[3] ; Yao Feng[2] ; Fu Da[4,5] ; Liang Yajun[1] ; Zhang Peiyuan[1] ; Xiong Hua[6] ; Hu Guohong[1] ;
单位： [1]Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [2]Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China. [3]National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, China. [4]Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. [5]General Surgery, Ruijin Hospital & Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. [6]Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
出处：
DOI： 10.1038/s41421-022-00507-x
ISSN：

摘要：
Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has shown durable clinical benefits in lung cancer. However, many patients respond poorly to ICB treatment, underscoring an incomplete understanding of PD-L1 regulation and therapy resistance. Here, we find that MTSS1 is downregulated in lung adenocarcinoma, leading to PD-L1 upregulation, impairment of CD8+ lymphocyte function, and enhanced tumor progression. MTSS1 downregulation correlates with improved ICB efficacy in patients. Mechanistically, MTSS1 interacts with the E3 ligase AIP4 for PD-L1 monoubiquitination at Lysine 263, leading to PD-L1 endocytic sorting and lysosomal degradation. In addition, EGFR-KRAS signaling in lung adenocarcinoma suppresses MTSS1 and upregulates PD-L1. More importantly, combining AIP4-targeting via the clinical antidepressant drug clomipramine and ICB treatment improves therapy response and effectively suppresses the growth of ICB-resistant tumors in immunocompetent mice and humanized mice. Overall, our study discovers an MTSS1-AIP4 axis for PD-L1 monoubiquitination and reveals a potential combinatory therapy with antidepressants and ICB.© 2023. The Author(s).

基金：
National Key R&D Program of China (2020YFA0112300), the National Natural Science Foundation of China (81725017 and 81872367), the Shanghai Committee of Science and Technology (19JC1416100) and the Youth Innovation Promotion Association of the Chinese Academy of Sciences
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外文
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出版当年[2022]版：
大类 | 1 区 生物学
小类 | 1 区 细胞生物学
最新[2025]版：
大类 | 1 区 生物学
小类 | 1 区 细胞生物学
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出版当年[2021]版：
Q1 CELL BIOLOGY
最新[2023]版：
Q1 CELL BIOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

第一作者：
第一作者单位： [1]Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
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推荐引用方式(GB/T 7714)：
Wang Yuan,Jia Zhenchang,Liang Chenxi,et al.MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation[J].CELL DISCOVERY.2023,9(1):doi:10.1038/s41421-022-00507-x.
APA：
Wang Yuan,Jia Zhenchang,Liang Chenxi,He Yunfei,Cong Min...&Hu Guohong.(2023).MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation.CELL DISCOVERY,9,(1)
MLA：
Wang Yuan,et al."MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation".CELL DISCOVERY 9..1(2023)

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