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

Nagaraj Kerur; Shinichi Fukuda; Daipayan Banerjee; Younghee Kim; Dongxu Fu; Ivana Apicella; Akhil Varshney; Reo Yasuma; Benjamin J. Fowler; Elmira Baghdasaryan; Kenneth M. Marion; Xiwen Huang; Tetsuhiro Yasuma; Yoshio Hirano; Vlad Serbulea; Meenakshi Ambati; Vidya L. Ambati; Yuji Kajiwara; Kameshwari Ambati; Shuichiro Hirahara; Ana Bastos-Carvalho; Yuichiro Ogura; Hiroko Terasaki; Tetsuro Oshika; Kyung Bo Kim; David R. Hinton; Norbert Leitinger; John C. Cambier; Joseph D. Buxbaum; M. Cristina Kenney; S. Michal Jazwinski; Hiroshi Nagai; Isao Hara; A. Phillip West; Katherine A. Fitzgerald; Srini Vas R. Sadda; Bradley D. Gelfand; Jayakrishna Ambati

doi:10.1038/nm.4450

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

Nagaraj Kerur, Shinichi Fukuda, Daipayan Banerjee, Younghee Kim, Dongxu Fu, Ivana Apicella, Akhil Varshney, Reo Yasuma, Benjamin J. Fowler, Elmira Baghdasaryan, Kenneth M. Marion, Xiwen Huang, Tetsuhiro Yasuma, Yoshio Hirano, Vlad Serbulea, Meenakshi Ambati, Vidya L. Ambati, Yuji Kajiwara, Kameshwari Ambati, Shuichiro HiraharaAna Bastos-Carvalho, Yuichiro Ogura, Hiroko Terasaki, Tetsuro Oshika, Kyung Bo Kim, David R. Hinton, Norbert Leitinger, John C. Cambier, Joseph D. Buxbaum, M. Cristina Kenney, S. Michal Jazwinski, Hiroshi Nagai, Isao Hara, A. Phillip West, Katherine A. Fitzgerald, Srini Vas R. Sadda, Bradley D. Gelfand, Jayakrishna Ambati

Research output: Contribution to journal › Article › peer-review

217 Scopus citations

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-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.

Original language	English
Pages (from-to)	50-61
Number of pages	12
Journal	Nature Medicine
Volume	24
Issue number	1
DOIs	https://doi.org/10.1038/nm.4450
State	Published - Jan 1 2018

Bibliographical note

Publisher Copyright:
© 2018 Nature America, Inc., part of Springer Nature. All rights reserved.

Funding

Funders	Funder number
National Institute of General Medical Sciences	T32GM007055
National Institute of General Medical Sciences

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm.4450

Cite this

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, 24(1), 50-61. https://doi.org/10.1038/nm.4450

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title = "CGAS drives noncanonical-inflammasome activation in age-related macular degeneration",

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-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.",

author = "Nagaraj Kerur and Shinichi Fukuda and Daipayan Banerjee and Younghee Kim and Dongxu Fu and Ivana Apicella and Akhil Varshney and Reo Yasuma and Fowler, {Benjamin J.} and Elmira Baghdasaryan and Marion, {Kenneth M.} and Xiwen Huang and Tetsuhiro Yasuma and Yoshio Hirano and Vlad Serbulea and Meenakshi Ambati and Ambati, {Vidya L.} and Yuji Kajiwara and Kameshwari Ambati and Shuichiro Hirahara and Ana Bastos-Carvalho and Yuichiro Ogura and Hiroko Terasaki and Tetsuro Oshika and Kim, {Kyung Bo} and Hinton, {David R.} and Norbert Leitinger and Cambier, {John C.} and Buxbaum, {Joseph D.} and {Cristina Kenney}, M. and {Michal Jazwinski}, S. and Hiroshi Nagai and Isao Hara and {Phillip West}, A. and Fitzgerald, {Katherine A.} and Sadda, {Srini Vas R.} and Gelfand, {Bradley D.} and Jayakrishna Ambati",

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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 2018, 'CGAS drives noncanonical-inflammasome activation in age-related macular degeneration', Nature Medicine, vol. 24, no. 1, pp. 50-61. https://doi.org/10.1038/nm.4450

TY - JOUR

T1 - CGAS drives noncanonical-inflammasome activation in age-related macular degeneration

AU - Kerur, Nagaraj

AU - Fukuda, Shinichi

AU - Banerjee, Daipayan

AU - Kim, Younghee

AU - Fu, Dongxu

AU - Apicella, Ivana

AU - Varshney, Akhil

AU - Yasuma, Reo

AU - Fowler, Benjamin J.

AU - Baghdasaryan, Elmira

AU - Marion, Kenneth M.

AU - Huang, Xiwen

AU - Yasuma, Tetsuhiro

AU - Hirano, Yoshio

AU - Serbulea, Vlad

AU - Ambati, Meenakshi

AU - Ambati, Vidya L.

AU - Kajiwara, Yuji

AU - Ambati, Kameshwari

AU - Hirahara, Shuichiro

AU - Bastos-Carvalho, Ana

AU - Ogura, Yuichiro

AU - Terasaki, Hiroko

AU - Oshika, Tetsuro

AU - Kim, Kyung Bo

AU - Hinton, David R.

AU - Leitinger, Norbert

AU - Cambier, John C.

AU - Buxbaum, Joseph D.

AU - Cristina Kenney, M.

AU - Michal Jazwinski, S.

AU - Nagai, Hiroshi

AU - Hara, Isao

AU - Phillip West, A.

AU - Fitzgerald, Katherine A.

AU - Sadda, Srini Vas R.

AU - Gelfand, Bradley D.

AU - Ambati, Jayakrishna

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

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