Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Medical Innovation Center (Taizhou) of Peking University, Taizhou 225316, China.
Proc Natl Acad Sci U S A. 2024 Oct 8;121(41):e2320591121. doi: 10.1073/pnas.2320591121. Epub 2024 Oct 3.
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.
化疗耐药性仍然是限制癌症治疗长期疗效的一个重大障碍，需要进一步研究其潜在机制。在这里，我们发现化疗药物诱导的 DNA 片段通过溶酶体触发 cGAS 的降解，cGAS 是一种有效的双链 DNA (dsDNA) 传感器。在机制上，溶酶体定位蛋白 LAMTOR1 上调，并且在暴露于 DNA 片段时，LAMTOR1 和 cGAS 之间的相互作用增强，通过受体蛋白 p62 促进 cGAS 在溶酶体中的积累和消化。LAMTOR1 缺失增加了 cGAS 的丰度，并通过诱导细胞质 DNA 刺激后产生 I 型干扰素促进 cGAS-STING 途径的激活。LAMTOR1 的缺失与免疫疗法和化疗协同作用，通过促进有效 T 淋巴细胞的浸润来抑制肿瘤生长和延长荷瘤小鼠的生存时间。因此，我们的研究揭示了 cGAS 丰度的调节，并提供了一种通过靶向 LAMTOR1 克服化疗耐药性的潜在策略。
