The DOI matches its Crossref record; 78 of the 78 references it cites were found in a registry or an index.
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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Cites
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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
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- 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., . . . Ambati, J. (2018). cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nature Medicine. https://doi.org/10.1038/nm.4450
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