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LAMTOR1 ablation impedes cGAS degradation caused by chemotherapy and promotes antitumor immunity
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2024-10-03 , DOI: 10.1073/pnas.2320591121 Juntao Bie, Yutong Li, Chen Song, Qiaoyou Weng, Long Zhao, Li Su, Zhongwei Zhao, Yingjiang Ye, Zhanlong Shen, Jiansong Ji, Jianyuan Luo
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2024-10-03 , DOI: 10.1073/pnas.2320591121 Juntao Bie, Yutong Li, Chen Song, Qiaoyou Weng, Long Zhao, Li Su, Zhongwei Zhao, Yingjiang Ye, Zhanlong Shen, Jiansong Ji, Jianyuan Luo
Chemotherapy resistance remains a significant obstacle that limits the long-term efficacy of cancer therapy, necessitating further investigations into the underlying mechanisms. Here, we find that DNA fragments induced by chemotherapeutic agents trigger the degradation of cGAS, a potent double-strand DNA (dsDNA) sensor, by lysosomes. Mechanically, the lysosome-localized protein LAMTOR1 is up-regulated, and the interaction between LAMTOR1 and cGAS is enhanced upon exposure to DNA fragments, boosting the accumulation and digestion of cGAS in lysosomes through the receptor protein p62. LAMTOR1 deficiency increases cGAS abundance and promotes activation of the cGAS–STING pathway, leading to subsequent production of type I interferons induced by cytosolic DNA stimulation. Loss of LAMTOR1 synergizes with immunotherapy and chemotherapy to inhibit tumor growth and prolong the survival time of tumor-bearing mice by promoting the infiltration of effective T lymphocytes. Thus, our study reveals a regulation of cGAS abundance and provides a potential strategy to overcome chemotherapy resistance by targeting LAMTOR1.
更新日期：2024-10-03
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