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cGAS drives noncanonical-inflammasome activation in age-related macular degeneration
Open accessAbstract
Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D–dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.
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Metadata
- Authors
- Kerur, N., Fukuda, S., Banerjee, D., Kim, Y., Fu, D., Apicella, I., Varshney, A., Yasuma, R., Fowler, B. J., Baghdasaryan, E., Marion, K. M., Huang, X., Yasuma, T., Hirano, Y., Serbulea, V., Ambati, M., Ambati, V. L., Kajiwara, Y., Ambati, K., Hirahara, S., Bastos-Carvalho, A., Ogura, Y., Terasaki, H., Oshika, T., Kim, K. B., Hinton, D. R., Leitinger, N., Cambier, J. C., Buxbaum, J. D., Kenney, M. C., Jazwinski, S. M., Nagai, H., Hara, I., West, A. P., Fitzgerald, K. A., Sadda, S. R., Gelfand, B. D., & Ambati, J.
- Venue
- Nature Medicine
- Published
- 2017-11-27
- Volume
- 24
- Issue
- 1
- Pages
- 50-61
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2768387192
- Cited by
- 286
- References
- 78
- FWCI
- 7.47
- Type
- journal article
- Language
- en
- Open access
- green
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
