ADAR1 Zα Domain P195A Mutation Activates the MDA5-dependent RNA-sensing Signaling Pathway in Brain Without Decreasing Overall RNA Editing

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 Jul 8

PMID 37421629

Authors

Xinfeng Guo

Silvia Liu

Yi Sheng

Mazen Zenati

Timothy Billiar

Alan Herbert

Qingde Wang

Affiliations

Soon will be listed here.

Abstract

Variants of the RNA-editing enzyme ADAR1 cause Aicardi-Goutières syndrome (AGS), in which severe inflammation occurs in the brain due to innate immune activation. Here, we analyze the RNA-editing status and innate immune activation in an AGS mouse model that carries the Adar P195A mutation in the N terminus of the ADAR1 p150 isoform, the equivalent of the P193A human Zα variant causal for disease. This mutation alone can cause interferon-stimulated gene (ISG) expression in the brain, especially in the periventricular areas, reflecting the pathologic feature of AGS. However, in these mice, ISG expression does not correlate with an overall decrease in RNA editing. Rather, the enhanced ISG expression in the brain due to the P195A mutant is dose dependent. Our findings indicate that ADAR1 can regulate innate immune responses through Z-RNA binding without changing overall RNA editing.

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References

Hubbard N, Ames J, Maurano M, Chu L, Somfleth K, Gokhale N . ADAR1 mutation causes ZBP1-dependent immunopathology. Nature. 2022; 607(7920):769-775. PMC: 9339495. DOI: 10.1038/s41586-022-04896-7. View

Cingolani P, Patel V, Coon M, Nguyen T, Land S, Ruden D . Using Drosophila melanogaster as a Model for Genotoxic Chemical Mutational Studies with a New Program, SnpSift. Front Genet. 2012; 3:35. PMC: 3304048. DOI: 10.3389/fgene.2012.00035. View

Maroofian R, Sedmik J, Mazaheri N, Scala M, Zaki M, Keegan L . Biallelic variants in , encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy. J Med Genet. 2020; 58(7):495-504. PMC: 8327408. DOI: 10.1136/jmedgenet-2020-107048. View

Herbert A, Alfken J, Kim Y, Mian I, Nishikura K, Rich A . A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. Proc Natl Acad Sci U S A. 1997; 94(16):8421-6. PMC: 22942. DOI: 10.1073/pnas.94.16.8421. View

Herbert A . Mendelian disease caused by variants affecting recognition of Z-DNA and Z-RNA by the Zα domain of the double-stranded RNA editing enzyme ADAR. Eur J Hum Genet. 2019; 28(1):114-117. PMC: 6906422. DOI: 10.1038/s41431-019-0458-6. View

Schade M, Turner C, Lowenhaupt K, Rich A, Herbert A . Structure-function analysis of the Z-DNA-binding domain Zalpha of dsRNA adenosine deaminase type I reveals similarity to the (alpha + beta) family of helix-turn-helix proteins. EMBO J. 1999; 18(2):470-9. PMC: 1171140. DOI: 10.1093/emboj/18.2.470. View

Liu Y, George C, Patterson J, Samuel C . Functionally distinct double-stranded RNA-binding domains associated with alternative splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase. J Biol Chem. 1997; 272(7):4419-28. DOI: 10.1074/jbc.272.7.4419. View

Liang Z, Chalk A, Taylor S, Goradia A, Heraud-Farlow J, Walkley C . The phenotype of the most common human ADAR1p150 Zα mutation P193A in mice is partially penetrant. EMBO Rep. 2023; 24(5):e55835. PMC: 10157378. DOI: 10.15252/embr.202255835. View

de Reuver R, Verdonck S, Dierick E, Nemegeer J, Hessmann E, Ahmad S . ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. Nature. 2022; 607(7920):784-789. DOI: 10.1038/s41586-022-04974-w. View

10.

Crow Y, Stetson D . The type I interferonopathies: 10 years on. Nat Rev Immunol. 2021; 22(8):471-483. PMC: 8527296. DOI: 10.1038/s41577-021-00633-9. View

11.

Maurano M, Snyder J, Connelly C, Henao-Mejia J, Sidrauski C, Stetson D . Protein kinase R and the integrated stress response drive immunopathology caused by mutations in the RNA deaminase ADAR1. Immunity. 2021; 54(9):1948-1960.e5. PMC: 8446335. DOI: 10.1016/j.immuni.2021.07.001. View

12.

Brown 2nd B, Lowenhaupt K, Wilbert C, Hanlon E, Rich A . The zalpha domain of the editing enzyme dsRNA adenosine deaminase binds left-handed Z-RNA as well as Z-DNA. Proc Natl Acad Sci U S A. 2000; 97(25):13532-6. PMC: 17610. DOI: 10.1073/pnas.240464097. View

13.

Rice G, Kasher P, Forte G, Mannion N, Greenwood S, Szynkiewicz M . Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet. 2012; 44(11):1243-8. PMC: 4154508. DOI: 10.1038/ng.2414. View

14.

Hartner J, Schmittwolf C, Kispert A, Muller A, Higuchi M, Seeburg P . Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem. 2003; 279(6):4894-902. DOI: 10.1074/jbc.M311347200. View

15.

Inoue M, Nakahama T, Yamasaki R, Shibuya T, Kim J, Todo H . An Aicardi-Goutières Syndrome-Causative Point Mutation in Gene Invokes Multiorgan Inflammation and Late-Onset Encephalopathy in Mice. J Immunol. 2021; 207(12):3016-3027. DOI: 10.4049/jimmunol.2100526. View

16.

Herbert A, Schade M, Lowenhaupt K, Alfken J, Schwartz T, Shlyakhtenko L . The Zalpha domain from human ADAR1 binds to the Z-DNA conformer of many different sequences. Nucleic Acids Res. 1998; 26(15):3486-93. PMC: 147729. DOI: 10.1093/nar/26.15.3486. View

17.

Rice G, Patrick T, Parmar R, Taylor C, Aeby A, Aicardi J . Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet. 2007; 81(4):713-25. PMC: 2227922. DOI: 10.1086/521373. View

18.

Seeburg P, Higuchi M, Sprengel R . RNA editing of brain glutamate receptor channels: mechanism and physiology. Brain Res Brain Res Rev. 1998; 26(2-3):217-29. DOI: 10.1016/s0165-0173(97)00062-3. View

19.

Wang Q, Miyakoda M, Yang W, Khillan J, Stachura D, Weiss M . Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem. 2003; 279(6):4952-61. DOI: 10.1074/jbc.M310162200. View

20.

Hartner J, Walkley C, Lu J, Orkin S . ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol. 2008; 10(1):109-15. PMC: 2701568. DOI: 10.1038/ni.1680. View