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Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.

ABSTRACT: 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.

SUBMITTER: Fukuda S

PROVIDER: S-EPMC8480932 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.

Fukuda Shinichi S Narendran Siddharth S Varshney Akhil A Nagasaka Yosuke Y Wang Shao-Bin SB Ambati Kameshwari K Apicella Ivana I Pereira Felipe F Fowler Benjamin J BJ Yasuma Tetsuhiro T Hirahara Shuichiro S Yasuma Reo R Huang Peirong P Yerramothu Praveen P Makin Ryan D RD Wang Mo M Baker Kirstie L KL Marion Kenneth M KM Huang Xiwen X Baghdasaryan Elmira E Ambati Meenakshi M Ambati Vidya L VL Banerjee Daipayan D Bonilha Vera L VL Tolstonog Genrich V GV Held Ulrike U Ogura Yuichiro Y Terasaki Hiroko H Oshika Tetsuro T Bhattarai Deepak D Kim Kyung Bo KB Feldman Sanford H SH Aguirre J Ignacio JI Hinton David R DR Kerur Nagaraj N Sadda Srinivas R SR Schumann Gerald G GG Gelfand Bradley D BD Ambati Jayakrishna J

Science advances 20210929 40

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 t ...[more]

PMID: 34586848

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Project description:The gap in our understanding of the pathobiology of atrophic AMD (aAMD) is a barrier to developing new and effective therapies for geographic atrophy (GA) of the retinal pigment epithelium (RPE). Age-related decline in phagocytic function and impaired autophagy flux in RPE cause oxidized lipid-protein accumulation, accelerating complement-mediated inflammation and leading to RPE cell damage and apoptosis. Prominin-1 (Prom1), a glycosylated membrane protein, is essential for photoreceptor (PR) disk biogenesis and outer segment (OS) structure. However, Prom1 mutations are primarily implicated in macular diseases such as Stargardt disease 4 and bull’s eye macular dystrophies. The physiological impact of Prom1 mutations in the retina is not clear. We have shown earlier that Prom1 is a central regulator of autophagy in human RPE and identified Prom1 as an emerging player in RPE homeostasis. We propose to build upon these salient findings by assessing the central hypothesis that Prom1 plays a cell-autonomous role in the RPE and that defects in Prom1-dependent mTORC1-TFEB signaling impair RPE autophagy and lysosomal function, triggering mRPE degeneration and induction of epithelial-mesenchymal transition (EMT). This study investigated whether Prom1 is required for mouse RPE (mRPE) autophagy and phagocytosis, which are cellular processes essential for photoreceptor survival. Prom1-KO decreases autophagy flux, activates mTORC1, and concomitantly decreases transcription factor EB (TFEB) and Cathepsin-D activities in mRPE cells. In addition, Prom1-KO reduces the clearance of bovine photoreceptor outer segments in mRPE cells due to increased mTORC1 and reduced TFEB activities. Dysfunction of Prom1-dependent autophagy correlates with both a decrease in ZO-1 and E-cadherin and a concomitant increase in Vimentin, SNAI1, and ZEB1 levels, consistent with induction of epithelial-mesenchymal transition (EMT) in Prom1-KO mRPE cells. Transcriptomic analysis of Prom1-KO mouse RPE cells by RNA sequencing showed a list of 15 DEGs with high statistical significance in Prom1-KO vs. WT mRPE cells. GSEA and NES show significant upregulation of cell-cycle transcription factors (E2F and MYC targets, G2M checkpoint), mTORC1 signaling, unfolded protein response, reactive oxygen species, TNFA signaling via NF-kappaB, DNA repair, and oxidative phosphorylation pathways; whereas significant downregulation of apical junction and EMT pathways in Prom1-KO vs. WT mRPE cells. Our results demonstrate that Prom1-mTORC1-TFEB signaling is a central driver of cell-autonomous mRPE homeostasis. We show that Prom1-KO in mRPE leads to RPE defects similar to those seen in atrophic age-related macular degeneration and opens new avenues of investigation targeting Prom1 in retinal degenerative diseases.

Dataset Information

Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.

Publications

<i>Alu</i> complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.

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