CGAS drives noncanonical-inflammasome activation in age-related macular degeneration Article

Kerur, N, Fukuda, S, Banerjee, D et al. (2018). CGAS drives noncanonical-inflammasome activation in age-related macular degeneration . 24(1), 50-61. 10.1038/nm.4450

cited authors

  • Kerur, N; Fukuda, S; Banerjee, D; Kim, Y; Fu, D; Apicella, I; Varshney, A; Yasuma, R; Fowler, BJ; Baghdasaryan, E; Marion, KM; Huang, X; Yasuma, T; Hirano, Y; Serbulea, V; Ambati, M; Ambati, VL; Kajiwara, Y; Ambati, K; Hirahara, S; Bastos-Carvalho, A; Ogura, Y; Terasaki, H; Oshika, T; Kim, KB; Hinton, DR; Leitinger, N; Cambier, JC; Buxbaum, JD; Cristina Kenney, M; Michal Jazwinski, S; Nagai, H; Hara, I; Phillip West, A; Fitzgerald, KA; Sadda, SVR; Gelfand, BD; Ambati, J



  • 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.

publication date

  • January 1, 2018

Digital Object Identifier (DOI)

start page

  • 50

end page

  • 61


  • 24


  • 1