互补DNA在萎缩性黄斑变性中富集，并通过胞质内固有免疫引发视网膜色素上皮毒性。
complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.
作者信息
Fukuda Shinichi, Narendran Siddharth, Varshney Akhil, Nagasaka Yosuke, Wang Shao-Bin, Ambati Kameshwari, Apicella Ivana, Pereira Felipe, Fowler Benjamin J, Yasuma Tetsuhiro, Hirahara Shuichiro, Yasuma Reo, Huang Peirong, Yerramothu Praveen, Makin Ryan D, Wang Mo, Baker Kirstie L, Marion Kenneth M, Huang Xiwen, Baghdasaryan Elmira, Ambati Meenakshi, Ambati Vidya L, Banerjee Daipayan, Bonilha Vera L, Tolstonog Genrich V, Held Ulrike, Ogura Yuichiro, Terasaki Hiroko, Oshika Tetsuro, Bhattarai Deepak, Kim Kyung Bo, Feldman Sanford H, Aguirre J Ignacio, Hinton David R, Kerur Nagaraj, Sadda Srinivas R, Schumann Gerald G, Gelfand Bradley D, Ambati Jayakrishna
机构信息
Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
出版信息
Sci Adv. 2021 Oct;7(40):eabj3658. doi: 10.1126/sciadv.abj3658. Epub 2021 Sep 29.
Long interspersed nuclear element-1 (L1)–mediated reverse transcription (RT) of RNA into cytoplasmic complementary DNA (cDNA) has been implicated in retinal pigmented epithelium (RPE) degeneration. The mechanism of cDNA–induced cytotoxicity and its relevance to human disease are unknown. Here we report that cDNA is highly enriched in the RPE of human eyes with geographic atrophy, an untreatable form of age-related macular degeneration. We demonstrate that the DNA sensor cGAS engages cDNA to induce cytosolic mitochondrial DNA escape, which amplifies cGAS activation, triggering RPE degeneration via the inflammasome. The L1-extinct rice rat was resistant to RNA–induced cDNA synthesis and RPE degeneration, which were enabled upon L1-RT overexpression. Nucleoside RT inhibitors (NRTIs), which inhibit both L1-RT and inflammasome activity, and NRTI derivatives (Kamuvudines) that inhibit inflammasome, but not RT, both block cDNA toxicity, identifying inflammasome activation as the terminal effector of RPE degeneration.
长散在核元件1（L1）介导的RNA逆转录（RT）形成细胞质互补DNA（cDNA）与视网膜色素上皮（RPE）变性有关。cDNA诱导的细胞毒性机制及其与人类疾病的相关性尚不清楚。在此，我们报告cDNA在患有地图样萎缩的人眼RPE中高度富集，地图样萎缩是年龄相关性黄斑变性的一种无法治疗的形式。我们证明，DNA传感器cGAS与cDNA结合以诱导胞质线粒体DNA逃逸，这会放大cGAS激活，通过炎性小体触发RPE变性。L1缺失的稻鼠对RNA诱导的cDNA合成和RPE变性具有抗性，而L1-RT过表达则会导致这些情况。抑制L1-RT和炎性小体活性的核苷逆转录酶抑制剂（NRTIs）以及抑制炎性小体而非RT的NRTI衍生物（卡穆夫定）均能阻断cDNA毒性，确定炎性小体激活是RPE变性的终末效应器。
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