Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.
Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.
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DOI：
10.1126/sciadv.abj3658
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发表时间：
2021-10
期刊：
影响因子：
13.6
通讯作者：
Ambati J
中科院分区：
文献类型：
--
作者：
Fukuda S;Narendran S;Varshney A;Nagasaka Y;Wang SB;Ambati K;Apicella I;Pereira F;Fowler BJ;Yasuma T;Hirahara S;Yasuma R;Huang P;Yerramothu P;Makin RD;Wang M;Baker KL;Marion KM;Huang X;Baghdasaryan E;Ambati M;Ambati VL;Banerjee D;Bonilha VL;Tolstonog GV;Held U;Ogura Y;Terasaki H;Oshika T;Bhattarai D;Kim KB;Feldman SH;Aguirre JI;Hinton DR;Kerur N;Sadda SR;Schumann GG;Gelfand BD;Ambati J
内源性Alu cDNA触发年龄相关性黄斑变性中炎性小体介导的细胞死亡长散布的核元件-1（L1）介导的Alu RNA逆转录（RT）为胞质Alu互补DNA（cDNA）与视网膜色素上皮（RPE）变性有关。Alu cDNA诱导细胞毒性的机制及其与人类疾病的相关性尚不清楚。在这里，我们报告说，铝cDNA是高度富集在人类眼睛的视网膜色素上皮地图状萎缩，一种无法治愈的形式的年龄相关性黄斑变性。我们证明了DNA传感器cGAS与Alu cDNA接合以诱导胞质线粒体DNA逃逸，这放大了cGAS激活，通过炎性小体触发RPE变性。L1-灭绝的水稻大鼠对Alu RNA诱导的Alu cDNA合成和RPE变性具有抗性，这在L1-RT过表达时是可能的。抑制L1-RT和炎性小体活性的核苷RT抑制剂（NRTI）和抑制炎性小体但不抑制RT的NRTI衍生物（Kamuvudines）均阻断Alu cDNA毒性，从而鉴定炎性小体活化为RPE变性的末端效应物。
Endogenous Alu cDNA triggers inflammasome-mediated cell death in age-related macular degeneration. Long interspersed nuclear element-1 (L1)–mediated reverse transcription (RT) of Alu RNA into cytoplasmic Alu complementary DNA (cDNA) has been implicated in retinal pigmented epithelium (RPE) degeneration. The mechanism of Alu cDNA–induced cytotoxicity and its relevance to human disease are unknown. Here we report that Alu 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 Alu 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 Alu RNA–induced Alu 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 Alu cDNA toxicity, identifying inflammasome activation as the terminal effector of RPE degeneration.
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DOI：
10.1126/science.aac7442
发表时间：
2015-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hung T;Pratt GA;Sundararaman B;Townsend MJ;Chaivorapol C;Bhangale T;Graham RR;Ortmann W;Criswell LA;Yeo GW;Behrens TW
通讯作者：
Behrens TW
影响因子：
30.8
作者：
Dewannieux, M;Esnault, C;Heidmann, T
通讯作者：
Heidmann, T
影响因子：
4.4
作者：
Bonilha, Vera L.;Rayborn, Mary E.;Hollyfield, Joe G.
通讯作者：
Hollyfield, Joe G.
影响因子：
4.4
作者：
Grossniklaus, Hans E.;Nickerson, John M.;Berglin, Lennart
通讯作者：
Berglin, Lennart
影响因子：
30.5
作者：
Herzner AM;Hagmann CA;Goldeck M;Wolter S;Kübler K;Wittmann S;Gramberg T;Andreeva L;Hopfner KP;Mertens C;Zillinger T;Jin T;Xiao TS;Bartok E;Coch C;Ackermann D;Hornung V;Ludwig J;Barchet W;Hartmann G;Schlee M
通讯作者：
Schlee M