ADAR1在固有免疫和炎症中的调控作用

doi:10.13560/j.cnki.biotech.bull.1985.2025-0608

摘要/Abstract

摘要：

RNA特异性腺苷脱氨酶1（ADAR1）是RNA编辑的关键酶之一，能催化双链RNA（dsRNA）分子中的腺苷（A）转化为肌苷（I），在免疫调节、炎症反应等生理过程中发挥重要作用。ADAR1的免疫调控作用体现在双重机制：其一，通过RNA编辑修饰dsRNA结构，使其无法激活模式识别受体及下游效应蛋白，从而维持自身免疫耐受；其二，通过非编辑依赖性方式与RIG-I、MDA5等模式识别受体互作，间接调控NF-κB、IRF等信号分子的激活，进而影响促炎细胞因子的释放。在炎症反应中，ADAR1通过多条路径发挥抗炎效应。一方面，其可编辑病毒或自身dsRNA，降低dsRNA对RIG-I、MDA5的激活能力，从而抑制抗病毒炎症的过度激活；另一方面，ADAR1与PKR直接相互作用，抑制eIF2α磷酸化，以平衡细胞存活与炎症性死亡；同时，ADAR1还能通过编辑内源性dsRNA，阻断OAS-RNase L通路的异常RNA降解，避免由此触发的自身炎症；此外，ADAR1与ZBP1竞争性结合Z-RNA，抑制RIPK3-MLKL介导的程序性坏死，从而减轻由坏死引发的炎症反应。这些机制为开发针对炎症性疾病的治疗策略提供了理论基础，然而，上述研究多集中于人类和小鼠模型，其在家养动物炎症性疾病中的调控作用尚未明确。本文综述了ADAR1在炎症和免疫方面的研究，归纳了其重要调控机制，以期为揭示家养动物的炎症性疾病如奶牛乳房炎等的发病机理及开发有效防治策略奠定基础。

关键词: ADAR1, 固有免疫, 炎症, RNA编辑

Abstract:

RNA-specific adenosine deaminase 1 (ADAR1) is one of the key enzymes in RNA editing, capable of catalyzing the conversion of adenosine (A) in double-stranded RNA (dsRNA) molecules to inosine (I), and plays a significant role in physiological processes such as immune regulation and inflammatory responses. The immune regulatory effect of ADAR1 is reflected in a dual mechanism. Firstly, it modifies the structure of dsRNA through RNA editing to prevent it from activating pattern recognition receptors and downstream effector proteins, thereby maintaining autoimmune tolerance. Secondly, by interacting with pattern recognition receptors such as RIG-I and MDA5 in a non-editing-dependent manner, it indirectly regulates the activation of signaling molecules such as NF-κB and IRF, thereby affecting the release of pro-inflammatory cytokines. In the inflammatory response, ADAR1 exerts anti-inflammatory effects through multiple pathways. On the one hand, it can edit viral or endogenous dsRNA, reducing the activation ability of dsRNA for RIG-I and MDA5, thereby inhibiting the excessive activation of antiviral inflammation. On the other hand, ADAR1 interacts directly with PKR to inhibit the phosphorylation of eIF2α, thereby balancing cell survival and inflammatory death. Meanwhile, ADAR1 can also edit endogenous dsRNA to block abnormal RNA degradation in the OAS-RNase L pathway and avoid autoinflammation triggered thereby. Furthermore, ADAR1 competes with ZBP1 for binding to Z-RNA, inhibiting RIPK3-MLKL-mediated programmed necrosis, thereby alleviating the inflammatory response caused by necrosis. These mechanisms provide a theoretical basis for the development of therapeutic strategies for inflammatory diseases. However, most of the above-mentioned studies have focused on human and mouse models, and their regulatory roles in inflammatory diseases in domestic animals remain unclear. Given the significant impact of inflammatory diseases on the livestock economy, this paper reviews the research on ADAR1 in terms of inflammation and immunity, and summarizes its important regulatory mechanisms, with the aim of laying the foundation for revealing the pathogenesis of inflammatory diseases in domestic animals such as mastitis in dairy cows and developing effective prevention and treatment strategies.

Key words: ADAR1, innate immunity, inflammation, RNA editing

李慧慧, 王书节, 康晓龙. ADAR1在固有免疫和炎症中的调控作用[J]. 生物技术通报, 2026, 42(1): 42-50.

LI Hui-hui, WANG Shu-jie, KANG Xiao-long. The Role of RNA-specific Adenosine Deaminase 1 in Innate Immunity and Inflammation[J]. Biotechnology Bulletin, 2026, 42(1): 42-50.

图/表 2

图1 病毒感染时ADAR1两个亚型的表达与作用A：未感染病毒时；B：感染病毒前期；C：感染病毒后期。IFN-α/β：Ⅰ型IFN

Fig. 1 Expression and function of two subtypes of ADAR1 in virus infectionA: When the virus is not infected. B: The early stage of viral infection. C: The late stage of viral infection. IFN-α/β: Type I IFN

图2 ADAR1在固有免疫中的作用IRF3/IRF7：转录因子；NF-κB：核因子-κB；IFN-Ⅰ：I型IFN；IFNAR：IFN的受体；ISGs：干扰素刺激基因；ISGF3：ISGF3（interferon-stimulated gene factor 3）是一种转录因子复合物，由STAT1、STAT2和IRF9组成

Fig. 2 Role of ADAR1 in innate immunityIRF3/IRF7: Transcription factor; NF-κB: nuclear factor-κB; IFN-Ⅰ: type I IFN; IFNAR: receptor for IFN; ISGs, interferon stimulating gene; ISGF3: interferon-stimulated gene factor 3 (ISGF3) is a transcription factor complex composed of STAT1, STAT2, and IRF9

参考文献 59

[1]	Song YL, Yang WB, Fu Q, et al. irCLASH reveals RNA substrates recognized by human ADARs [J]. Nat Struct Mol Biol, 2020, 27(4): 351-362.
[2]	Zhong YH, Zhong X, Qiao LJ, et al. Zα domain proteins mediate the immune response [J]. Front Immunol, 2023, 14: 1241694.
[3]	Bahn JH, Ahn J, Lin XZ, et al. Genomic analysis of ADAR1 binding and its involvement in multiple RNA processing pathways [J]. Nat Commun, 2015, 6: 6355.
[4]	Song B, Shiromoto Y, Minakuchi M, et al. The role of RNA editing enzyme ADAR1 in human disease [J]. Wires RNA, 2022, 13(1): e1665.
[5]	Kleinova R, Rajendra V, Leuchtenberger AF, et al. The ADAR1 editome reveals drivers of editing-specificity for ADAR1-isoforms [J]. Nucleic Acids Res, 2023, 51(9): 4191-4207.
[6]	Ashley CN, Broni E, Miller WA. ADAR family proteins: a structural review [J]. Curr Issues Mol Biol, 2024, 46(5): 3919-3945.
[7]	Matthews MM, Thomas JM, Zheng YX, et al. Structures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity [J]. Nat Struct Mol Biol, 2016, 23(5): 426-433.
[8]	Fisher AJ, Beal PA. Structural perspectives on adenosine to inosine RNA editing by ADARs [J]. Mol Ther Nucleic Acids, 2024, 35(3): 102284.
[9]	Quin J, Sedmík J, Vukić D, et al. ADAR RNA modifications, the epitranscriptome and innate immunity [J]. Trends Biochem Sci, 2021, 46(9): 758-771.
[10]	Song CZ, Sakurai M, Shiromoto Y, et al. Functions of the RNA editing enzyme ADAR1 and their relevance to human diseases [J]. Genes, 2016, 7(12): 129.
[11]	Xu L-D, Öhman M. ADAR1 editing and its role in cancer [J]. Genes, 2019, 10(1): 12.
[12]	Liddicoat BJ, Piskol R, Chalk AM, et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself [J]. Science, 2015, 349(6252): 1115-1120.
[13]	Samuel CE. Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA-triggered innate immune responses [J]. J Biol Chem, 2019, 294(5): 1710-1720.
[14]	Yuan J, Xu L, Bao HJ, et al. Biological roles of A-to-I editing: implications in innate immunity, cell death, and cancer immunotherapy [J]. J Exp Clin Cancer Res, 2023, 42(1): 149.
[15]	Adamczak D, Fornalik M, Małkiewicz A, et al. ADAR1 expression in different cancer cell lines and its change under heat shock [J]. J Appl Genet, 2024: 149.
[16]	Szymczak F, Cohen-Fultheim R, Thomaidou S, et al. ADAR1-dependent editing regulates human β cell transcriptome diversity during inflammation [J]. Front Endocrinol, 2022, 13: 1058345.
[17]	Valentine A, Bosart K, Bush W, et al. Identification and characterization of ADAR1 mutations and changes in gene expression in human cancers [J]. Cancer Genet, 2024, 288/289: 82-91.
[18]	Mboukou A, Rajendra V, Messmer S, et al. Dimerization of ADAR1 modulates site-specificity of RNA editing [J]. Nat Commun, 2024, 15: 10051.
[19]	Roth SH, Danan-Gotthold M, Ben-Izhak M, et al. Increased RNA editing may provide a source for autoantigens in systemic lupus erythematosus [J]. Cell Rep, 2018, 23(1): 50-57.
[20]	Nakahama T, Kawahara Y. The RNA-editing enzyme ADAR1: a regulatory hub that tunes multiple dsRNA-sensing pathways [J]. Int Immunol, 2023, 35(3): 123-133.
[21]	Bazak L, Haviv A, Barak M, et al. A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes [J]. Genome Res, 2014, 24(3): 365-376.
[22]	Nishikura K. A-to-I editing of coding and non-coding RNAs by ADARs [J]. Nat Rev Mol Cell Biol, 2016, 17(2): 83-96.
[23]	Mu JQ, Wu C, Xu KM, et al. Conformational reorganization and phase separation drive hyper-editing of ADR-2-ADBP-1 complex [J]. Nucleic Acids Res, 2025, 53(5): gkaf148.
[24]	Uzonyi A, Nir R, Shliefer O, et al. Deciphering the principles of the RNA editing code via large-scale systematic probing [J]. Mol Cell, 2021, 81(11): 2374-2387.e3.
[25]	Rehwinkel J, Mehdipour P. ADAR1: from basic mechanisms to inhibitors [J]. Trends Cell Biol, 2025, 35(1): 59-73.
[26]	Deffit SN, Hundley HA. To edit or not to edit: regulation of ADAR editing specificity and efficiency [J]. Wiley Interdiscip Rev RNA, 2016, 7(1): 113-127.
[27]	Sharma M, Wagh P, Shinde T, et al. Exploring the role of pattern recognition receptors as immunostimulatory molecules [J]. Immunity Inflam & Disease, 2025, 13(5): e70150.
[28]	Chen RC, Zou J, Chen JW, et al. Pattern recognition receptors: function, regulation and therapeutic potential [J]. Signal Transduct Target Ther, 2025, 10(1): 216.
[29]	Lamers MM, van den Hoogen BG, Haagmans BL. ADAR1: “editor-in-chief” of cytoplasmic innate immunity [J]. Front Immunol, 2019, 10: 1763.
[30]	Sikorska J, Wyss DF. Recent developments in understanding RIG-I’s activation and oligomerization [J]. Sci Prog, 2024, 107(3): 368504241265182.
[31]	Liu SQ, Cai X, Wu JX, et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation [J]. Science, 2015, 347(6227): aaa2630.
[32]	Ivashkiv LB, Donlin LT. Regulation of type I interferon responses [J]. Nat Rev Immunol, 2014, 14(1): 36-49.
[33]	Sampaio NG, Chauveau L, Hertzog J, et al. The RNA sensor MDA5 detects SARS-CoV-2 infection [J]. Sci Rep, 2021, 11(1): 13638.
[34]	Yang SY, Deng P, Zhu ZW, et al. Adenosine deaminase acting on RNA 1 limits RIG-I RNA detection and suppresses IFN production responding to viral and endogenous RNAs [J]. J Immunol, 2014, 193(7): 3436-3445.
[35]	Jiang YF, Zhang HY, Wang J, et al. Exploiting RIG-I-like receptor pathway for cancer immunotherapy [J]. J Hematol Oncol, 2023, 16(1): 8.
[36]	Dempsey LA. ADAR1 regulates mda5-MAVS [J]. Nat Immunol, 2016, 17(1): 47.
[37]	Shiromoto Y, Sakurai M, Minakuchi M, et al. ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells [J]. Nat Commun, 2021, 12(1): 1654.
[38]	Kim JI, Nakahama T, Yamasaki R, et al. RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain [J]. PLoS Genet, 2021, 17(5): e1009516.
[39]	Deng P, Khan A, Jacobson D, et al. Adar RNA editing-dependent and-independent effects are required for brain and innate immune functions in Drosophila [J]. Nat Commun, 2020, 11(1): 1580.
[40]	Gal-Ben-Ari S, Barrera I, Ehrlich M, et al. PKR: a kinase to remember [J]. Front Mol Neurosci, 2019, 11: 480.
[41]	Hu SB, Heraud-Farlow J, Sun T, et al. ADAR1p150 prevents MDA5 and PKR activation via distinct mechanisms to avert fatal autoinflammation [J]. bioRxiv, 2023: 2023.01.25.525475.
[42]	Gannon HS, Zou T, Kiessling MK, et al. Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells [J]. Nat Commun, 2018, 9(1): 5450.
[43]	Pestal K, Funk CC, Snyder JM, et al. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development [J]. Immunity, 2015, 43(5): 933-944.
[44]	Sinigaglia K, Cherian A, Du QP, et al. An ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA inhibits PKR activation [J]. Cell Rep, 2024, 43(8): 114618.
[45]	Clerzius G, Gélinas JF, Daher A, et al. ADAR1 interacts with PKR during human immunodeficiency virus infection of lymphocytes and contributes to viral replication [J]. J Virol, 2009, 83(19): 10119-10128.
[46]	Toth AM, Li ZQ, Cattaneo R, et al. RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR [J]. J Biol Chem, 2009, 284(43): 29350-29356.
[47]	Gélinas JF, Clerzius G, Shaw E, et al. Enhancement of replication of RNA viruses by ADAR1 via RNA editing and inhibition of RNA-activated protein kinase [J]. J Virol, 2011, 85(17): 8460-8466.
[48]	Wang YB, Holleufer A, Gad HH, et al. Length dependent activation of OAS proteins by dsRNA [J]. Cytokine, 2020, 126: 154867.
[49]	Daou S, Talukdar M, Tang JL, et al. A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency [J]. Proc Natl Acad Sci USA, 2020, 117(40): 24802-24812.
[50]	Li YZ, Banerjee S, Goldstein SA, et al. Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line [J]. eLife, 2017, 6: e25687.
[51]	Jiao HP, Wachsmuth L, Kumari S, et al. Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation [J]. Nature, 2020, 580(7803): 391-395.
[52]	Devos M, Tanghe G, Gilbert B, et al. Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation [J]. J Exp Med, 2020, 217(7): e20191913.
[53]	Kesavardhana S, Subbarao Malireddi RK, Burton AR, et al. The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development [J]. J Biol Chem, 2020, 295(24): 8325-8330.
[54]	Chen XY, Dai YH, Wan XX, et al. ZBP1-mediated necroptosis: mechanisms and therapeutic implications [J]. Molecules, 2022, 28(1): 52.
[55]	Zhan JH, Wang JS, Liang YQ, et al. Apoptosis dysfunction: unravelling the interplay between ZBP1 activation and viral invasion in innate immune responses [J]. Cell Commun Signal, 2024, 22(1): 149.
[56]	Karki R, Sundaram B, Sharma BR, et al. ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis [J]. Cell Rep, 2021, 37(3): 109858.
[57]	Jiao HP, Wachsmuth L, Wolf S, et al. ADAR1 averts fatal type I interferon induction by ZBP1 [J]. Nature, 2022, 607(7920): 776-783.
[58]	de Reuver R, Verdonck S, Dierick E, et al. ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation [J]. Nature, 2022, 607(7920): 784-789.
[59]	Zhang YG, Zhang JY, Xue YC. ADAR1: a mast regulator of aging and immunity [J]. Signal Transduct Target Ther, 2023, 8(1): 7.