RNA-Editing Enzyme ADAR1 p150 Isoform Is Critical for Germinal Center B Cell Response [IMMUNE REGULATION]

Key Points

ADAR1 p150 but not the p110 isoform controls the GC response.

ADAR1 regulates the GC response partially through the MDA5 but not the PKR or RNase L pathway.

The dsRNA-binding but not the RNA-editing activity of ADAR1 is critical for the GC response.

Abstract

Adenosine deaminase acting on RNA (ADAR)1 is the principal enzyme for adenosine-to-inosine editing, an RNA modification–avoiding cytosolic nucleic acid sensor’s activation triggered by endogenous dsRNAs. Two ADAR1 isoforms exist in mammals, a longer IFN-inducible and mainly cytoplasm-localized p150 isoform and a shorter constitutively expressed and primarily nucleus-localized p110 isoform. Studies of ADAR1 mutant mice have demonstrated that ADAR1 is essential for multiple physiological processes, including embryonic development, innate immune response, and B and T lymphocyte development. However, it remained unknown whether ADAR1 plays a role in the humoral immune response. In this study, we conditionally delete Adar1 in activated B cells and show that ADAR1-deficient mice have a defective T cell–dependent Ab response and diminished germinal center (GC) B cells. Using various double mutant mice concurrently deficient in ADAR1 and different downstream dsRNA sensors, we demonstrate that ADAR1 regulates the GC response by preventing hyperactivation of the melanoma differentiation-associated protein 5 (MDA5) but not the protein kinase R or RNase L pathway. We also show that p150 is exclusively responsible for ADAR1’s function in the GC response, and the p110 isoform cannot substitute for the p150’s role, even when p110 is constitutively expressed in the cytoplasm. We further demonstrated that the dsRNA-binding but not the RNA-editing activity is required for ADAR1’s function in the GC response. Thus, our data suggest that the ADAR1 p150 isoform plays a crucial role in regulating the GC B cell response.

Footnotes

This work was supported by Guangdong Basic and Applied Basic Research Foundation Grant 2020A1515010262, National Natural Science Foundation of China Grant 32170882, Shenzhen Science and Technology Innovation Commission Grant JCYJ20190809161807432, and by the Agency for Science Technology and Research, Singapore.

X.O. conceived the study. Yuxing Li, X.O., and S.X. designed the research and wrote the paper. Yan Li designed the research and provided constructive suggestions. Yuxing Li performed most of the experiments. G.-X.R. analyzed the RNA-seq data. W.C. performed the immunofluorescence microscopy experiments. H.H. performed the plasmid construction. R.Z. and J.W. performed the animal work.

The online version of this article contains supplemental material.

Abbreviations used in this article:

ADARadenosine deaminase acting on RNAAIDactivation-induced cytidine deaminaseASCAb-secreting cellA-to-Iadenosine-to-inosineBMbone marrowCGGchicken γ-globulinDKOdouble KOdsRBDdsRNA-binding domainDZdark zoneFr.fractionGCgerminal centerGOGene OntologyHAhemagglutininKIknock-inKOknockoutLZlight zoneMAVSmitochondrial antiviral signaling proteinMDA5melanoma differentiation-associated protein 5NESnuclear export sequenceNIP(4-hydroxy-5-indo-3-nitrophenyl)acetylNP4-hydroxy-3-nitrophenyl-acetylPKRprotein kinase RRNA-seqRNA-sequencingTDT cell–dependentWTwild-typeReceived February 22, 2022.Accepted July 11, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

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