cGAS drives noncanonical-inflammasome activation in age-related macular degeneration.
Overview
Research
Identity
Additional Document Info
Other
View All
Overview
abstract
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- 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-, 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.
published proceedings
Nat Med
altmetric score
176.35
author list (cited authors)
Kerur, N., Fukuda, S., Banerjee, D., Kim, Y., Fu, D., Apicella, I., ... Ambati, J.
citation count
165
complete list of authors
Kerur, Nagaraj||Fukuda, Shinichi||Banerjee, Daipayan||Kim, Younghee||Fu, Dongxu||Apicella, Ivana||Varshney, Akhil||Yasuma, Reo||Fowler, Benjamin J||Baghdasaryan, Elmira||Marion, Kenneth M||Huang, Xiwen||Yasuma, Tetsuhiro||Hirano, Yoshio||Serbulea, Vlad||Ambati, Meenakshi||Ambati, Vidya L||Kajiwara, Yuji||Ambati, Kameshwari||Hirahara, Shuichiro||Bastos-Carvalho, Ana||Ogura, Yuichiro||Terasaki, Hiroko||Oshika, Tetsuro||Kim, Kyung Bo||Hinton, David R||Leitinger, Norbert||Cambier, John C||Buxbaum, Joseph D||Kenney, M Cristina||Jazwinski, S Michal||Nagai, Hiroshi||Hara, Isao||West, A Phillip||Fitzgerald, Katherine A||Sadda, SriniVas R||Gelfand, Bradley D||Ambati, Jayakrishna