Non-Coding RNA and Innate Immune Signal Regulation
摘要: 先天免疫对消除和控制感染至关重要，但不受控制的免疫反应可损伤宿主组织。机体免疫稳态的调节是一个精确的、复杂的过程，其中，非编码RNA是多种生物过程中的重要调控因子。目前研究表明微小RNA、长链非编码RNA通过调控先天免疫途径中的基因表达参与抗病毒反应、肿瘤免疫及自身免疫性疾病。通常情况下，微小RNA通过与mRNA的3′端非翻译区结合，在转录后水平调节基因表达，而长链非编码RNA则作为微小RNA的内源竞争RNA，抑制微小RNA与信使RNA的结合，发挥免疫调控作用。本综述总结了非编码RNA在先天免疫中的调节作用及其机制，为先天免疫的调节及免疫相关疾病的研究提供参考。同时，koko体育app 也展望了该领域未来的研究方向，包括新型非编码RNA的表达与成熟调控机制，以及非编码RNA在进化中的保守性等。Abstract: The innate immune system is critical to the elimination and control of infections. However, uncontrolled immune responses can cause indirect host-mediated tissue damage. The regulation of immune homeostasis is a complex but finely regulated process. ncRNAs have been increasingly identified as important regulators of a variety of biological processes. Recent research findings suggest that microRNAs and long non-coding RNAs participate in antiviral responses, tumor immunity, and autoimmune diseases by regulating gene expression in the innate immune pathways. MicroRNAs regulate gene expression at the post-transcriptional level by binding to the 3′ untranslated regions of mRNA, while long non-coding RNAs act as endogenous competing RNAs for microRNAs, inhibiting the binding of microRNAs and mRNAs. In this review, we summarized the regulatory role of non-coding RNAs in innate immunity and its mechanism to provide references for research in the regulation of innate immunity and immune-related diseases. In addition, we also reported discussions on the future research directions in the field, including the expression and maturation regulation mechanism of new non-coding RNAs, and the conservation of non-coding RNAs in evolution.
- Innate immune /
- ncRNA /
- miRNA /
图 2 ncRNA调控IRF3
Figure 2. 🌃 The regulatory mechanism of ncRNA on IRF3TLR: Toll-like receptor; TIR: Toll/IL-1R; TIRAP: TIR domain containing adaptor protein; IRAKs: IL-1 receptor associated kinase; TRAF: Tumor necrosis factor receptor-associated factor; IKKs: Inhibitor of NF-κB kinase complex; MAPKs: Mitogen-activated protein kinases; TBK1: TANK-binding kinase 1; IKKi: Inducible IκB Kinase; RIP1: Receptor-interacting protein 1; TAK1: Transforming growth factor β-activated kinase 1; TRAM: TRIF-related adaptor molecule; TRIF: TIR-domain-containing adaptor protein inducing IFN-β; OPTN: Optineurin; IRF: Interferon regulatory factor; PP2A: Protein phosphatase 2A; IFN: Interferon.
表 1 ncRNA调控先天免疫的机制
Table 1. ౠ Mechanism of ncRNA in regulating innate immunity
Regulation mechanism of ncRNA IRF ① miRNA: Directly binds to the 3′UTR of IRF mRNA and inhibits its expression; indirectly inhibits phosphorylation of IRF; inhibits the expression of upstream molecules of IRF, thereby inhibiting IRF. ② lncRNA: Competitively binds to miRNA to inhibit the binding of miRNA to target gene, thereby blocking miRNA function; competes with IRF3 to bind to the IFN-β promoter, interfering with the binding of IRF3 and IFN-β; binds to TBK1 kinase ubiquitination adaptor OPTN and stabilizes OPTN, promoting TLR-TBK1-dependent IRF3 phosphorylation. TRIF ① miRNA: Directly binds to the 3′UTR of TRIF mRNA and inhibits its expression. ② circRNA: Interacts with miRNA as a competitive endogenous RNA of TRIF mRNA. RIG-Ⅰ ① miRNA: Inhibits the expression of RIG-Ⅰ ubiquitination regulator TRIM25, thereby inhibiting the ubiquitination of RIG-Ⅰ; targets the 3′UTR of RIG-Ⅰ encoding gene DDX58 to inhibit the expression of RIG-Ⅰ; functions as ligand of RIG-Ⅰ, thereby contributing to immune enhancement. ② lncRNA: Competitively binds to the CTD of RIG-Ⅰ with viral RNA and limits its protein conformational changes, leaving RIG-Ⅰ in an inactive state; eliminates SFPQ’s transcription inhibitory effect on RIG-Ⅰ. M AVS ① miRNA: Directly binds to the 3′UTR of MAVS mRNA and inhibits its expression; indirectly regulates MAVS by targeting mitochondrial transporter. ② lncRNA: Competitively binds to miRNA, thereby blocking miRNA function. cGA S ① miRNA: Directly binds to the 3′UTR of cGAS mRNA and inhibits its expression; suppresses the mRNA level of cGAS by acting on epigenetic factors that maintain the expression of cGAS. ② lncRNA: Indirectly regulates the cGAS pathway by participating in the assembly of the HDP-RNP. STING ① miRNA: Directly binds to the 3′UTR of STING mRNA and inhibits its expression. ② lncRNA: Indirectly regulates STING transcription through CREB. ncRNA: Non-coding RNA; IRF: Interferon regulatory factor; miRNA: MicroRNA; 3′UTR: 3′ untranslated regions; lncRNA: Long non-coding RNA; IFN-β: Interferon-β; TBK1: TANK-bindingkinase; OPTN: Optineurin; TLR: Toll-like receptor; TRIF: TIR-domain-containing adaptor inducing interferon-β; circRNA: Circular RNA; RIG-Ⅰ: Retinoic acid‐inducible gene Ⅰ; TRIM25: Tripartite motif-containing protein 25; CTD: C-terminal domain; SFPQ: Splicing factor proline-and glutamine-rich protein; MAVS: Mitochondrial antiviral signaling; cGAS: Cyclic GMP-AMP synthase; HDP-RNP: HEXIM1-DNA-PK-paraspeckle components-ribonu-cleoprotein complex; STING: Stimulator of interferon genes; CREB: cAMP response element-binding protein.
 SLACK F J, CHINNAIYAN A M. The role of non-coding RNAs in oncology. Cell,2019,179(5): 1033–1055. doi:  WANG J, ZHU S, MENG N, et al. ncRNA-encoded peptides or proteins and cancer. Mol Ther,2019,27(10): 1718–1725. doi:  MORCHIKH M, CRIBIER A, RAFFEL R, et al. HEXIM1 and NEAT1 long non-coding RNA form a multi-subunit complex that regulates DNA-mediated innate immune response. Mol Cell, 2017, 67(3): 387-399.e385[2022-08-21]. .  SALMENA L, POLISENO L, TAY Y, et al. A ceRNA hypothesis: The rosetta stone of a hidden RNA language? Cell,2011,146(3): 353–358. doi:  HUANG X, FEJES TÓTH K, ARAVIN A A. piRNA biogenesis in drosophila melanogaster. Trends Genet,2017,33(11): 882–894. doi:  CHEN X, YANG T, WANG W, et al. Circular RNAs in immune responses and immune diseases. Theranostics,2019,9(2): 588–607. doi:  KIM J K, KIM T S, BASU J, et al. MicroRNA in innate immunity and autophagy during mycobacterial infection. Cell Microbiol, 2017, 19(1): e12687[2022-08-21]. .  WANG Y, WANG Y, LUO W, et al. Roles of long non-coding RNAs and emerging RNA-binding proteins in innate antiviral responses. Theranostics,2020,10(20): 9407–9424. doi:  QIN X W, HE J, YU Y, et al. The roles of mandarin fish STING in innate immune defense against infectious spleen and kidney necrosis virus infections. Fish Shellfish Immunol, 2020, 100: 80−89[2022-08-21]. .  VISHNOI A, RANI S. MiRNA biogenesis and regulation of diseases: An overview. Methods Mol Biol, 2017, 1509: 1−10[2022-08-21]. .  ZHU J, FU H, WU Y, et al. Function of lncRNAs and approaches to lncRNA-protein interactions. Sci China Life Sci,2013,56(10): 876–885. doi:  QU S, YANG X, LI X, et al. Circular RNA: A new star of noncoding RNAs. Cancer Lett,2015,365(2): 141–148. doi:  OZATA D M, GAINETDINOV I, ZOCH A, et al. Piwi-interacting RNAs: Small RNAs with big functions. Nat Rev Genet,2019,20(2): 89–108. doi:  ZHU L, LI J, GONG Y, et al. Exosomal tRNA-derived small RNA as a promising biomarker for cancer diagnosis. Mol Cancer, 2019, 18(1): 74[2022-08-21]. .  PARK J, AHN S H, SHIN M G, et al. TRNA-derived small RNAs: Novel epigenetic regulators. Cancers (Basel), 2020, 12(10): 2773[2022-08-21]. .  THAISS C A, ZMORA N, LEVY M, et al. The microbiome and innate immunity. Nature,2016,535(7610): 65–74. doi:  THAISS C A, LEVY M, ITAV S, et al. Integration of innate immune signaling. Trends Immunol,2016,37(2): 84–101. doi:  VIDYA M K, KUMAR V G, SEJIAN V, et al. Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol,2018,37(1): 20–36. doi:  MAHARJAN A S, PILLING D, GOMER R H. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation. Fibrogenesis Tissue Repair, 2010, 3: 23[2022-08-21]. .  PARK S R, KIM D J, HAN S H, et al. Diverse toll-like receptors mediate cytokine production by fusobacterium nucleatum and aggregatibacter actinomycetemcomitans in macrophages. Infect Immun,2014,82(5): 1914–1920. doi:  VÁZQUEZ-MENDOZA A, CARRERO J C, RODRIGUEZ-SOSA M. Parasitic infections: A role for C-type lectins receptors. Biomed Res Int, 2013, 2013: 456352[2022-08-21]. .  LIU B, GAO C. Regulation of MAVs activation through post-translational modifications. Curr Opin Immunol, 2018, 50: 75−81[2022-08-21]. .  CASTANIER C, ZEMIRLI N, PORTIER A, et al. MAVs ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type Ⅰ interferon production after activation of the antiviral RIG-Ⅰ-like receptors. BMC Biol, 2012, 10: 44[2022-08-21]. .  GRAY E E, WINSHIP D, SNYDER J M, et al. The AIM2-like receptors are dispensable for the interferon response to intracellular DNA. Immunity,2016,45(2): 255–266. doi:  HORNUNG V, HARTMANN R, ABLASSER A, et al. OAS proteins and cGAS: Unifying concepts in sensing and responding to cytosolic nucleic acids. Nat Rev Immunol,2014,14(8): 521–528. doi:  LI Z, CHEN B, FENG M, et al. MicroRNA-23b promotes avian leukosis virus subgroup j (ALV-j) replication by targeting IRF1. Sci Rep, 2015, 5: 10294[2022-08-21]. .  LEE Y S, BAO X, LEE H H, et al. Nc886, a novel suppressor of the type Ⅰ interferon response upon pathogen intrusion. Int J Mol Sci, 2021, 22(4): 2003[2022-08-21]. .  TANG Y, LUO X, CUI H, et al. MicroRNA-146a contributes to abnormal activation of the type Ⅰ interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum,2009,60(4): 1065–1075. doi:  ZHENG W, CHU Q, XU T. The long noncoding RNANARL regulates immune responses via microRNA-mediated NOD1 downregulation in teleost fish. J Biol Chem, 2021. 296: 100414[2022-08-21]. .  LI X, GUO G, LU M, et al. Long noncoding RNA lnc-MXA inhibits beta interferon transcription by forming RNA-DNA triplexes at its promoter. J Virol, 2019, 93(21): e00786−19[2022-08-21]. .  AZNAOUROVA M, JANGA H, SEFRIED S, et al. Noncoding RNA MAIL1 is an integral component of the TLR4-TRIF pathway. Proc Natl Acad Sci U S A,2020,117(16): 9042–9053. doi:  ZHENG W, CHU Q, YANG L, et al. Circular RNA circDtx1 regulates IRF3-mediated antiviral immune responses through suppression of mir-15a-5p-dependent TRIF downregulation in teleost fish. PLoS Pathog, 2021, 17(3): e1009438[2022-08-21]. .  LIU W, JIN Y, ZHANG W, et al. MiR-202-5p inhibits RIG-Ⅰ-dependent innate immune responses to rgnnv infection by targeting TRIM25 to mediate RIG-Ⅰ ubiquitination. Viruses, 2020, 12(3): 261[2022-08-21]. .  QIU Y, GENG X, BAN J, et al. MicroRNA-218 inhibits type Ⅰ interferon production and facilitates virus immune evasion via targeting RIG-Ⅰ. Biotechnol Appl Biochem,2020,67(3): 396–403. doi:  NAM R K, BENATAR T, AMEMIYA Y, et al. MiR-139 induces an interferon-β response in prostate cancer cells by binding to RIG-Ⅰ. Cancer Genomics Proteomics,2021,18(3): 197–206. doi:  JIANG M, ZHANG S, YANG Z, et al. Self-recognition of an inducible host lncRNA by RIG-Ⅰ feedback restricts innate immune response. Cell, 2018, 173(4): 906−919.e913[2022-08-21]. .  MA H, HAN P, YE W, et al. The long noncoding RNA NEAT1 exerts anti-hantaviral effects by acting as positive feedback for RIG-Ⅰ signaling. J Virol, 2017, 91(9): e02250−16[2022-08-21]. .  XU T, CHU Q, CUI J, et al. Inducible microRNA-3570 feedback inhibits the RIG-Ⅰ-dependent innate immune response to rhabdovirus in teleost fish by targeting MAVs/IPS-1. J Virol, 2018, 92(2): e01594−17[2022-08-21]. .  YASUKAWA K, KINOSHITA D, YAKU K, et al. The microRNAs miR-302b and miR-372 regulate mitochondrial metabolism via the SLC25A12 transporter, which controls MAVs-mediated antiviral innate immunity. J Biol Chem,2020,295(2): 444–457. doi:  CHU Q, XU T, ZHENG W, et al. Long noncoding RNA MARL regulates antiviral responses through suppression miR-122-dependent MAVs downregulation in lower vertebrates. PLoS Pathog, 2020, 16(7): e1008670[2022-08-21]. .  YU Q, CHU L, LI Y, et al. MiR-23a/b suppress cGAS-mediated innate and autoimmunity. Cell Mol Immunol,2021,18(5): 1235–1248. doi:  WU M Z, CHENG W C, CHEN S F, et al. MiR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS. Nat Cell Biol,2017,19(10): 1286–1296. doi:  XU T, CHU Q, CUI J. Rhabdovirus-inducible microRNA-210 modulates antiviral innate immune response via targeting STING/MITA in fish. J Immunol,2018,201(3): 982–994. doi:  CHEN J H, FENG D D, CHEN Y F, et al. Long non-coding RNAMALAT1 targeting STING transcription promotes bronchopulmonary dysplasia through regulation of CREB. J Cell Mol Med,2020,24(18): 10478–10492. doi:  NEGISHI H, TANIGUCHI T, YANAI H. The interferon (IFN) class of cytokines and the IFN regulatory factor (IRF) transcription factor family. Cold Spring Harb Perspect Biol, 2018, 10(11): a028423[2022-08-21]. .  ZHANG B C, ZHOU Z J, SUN L. Pol-miR-731, a teleost mirna upregulated by megalocytivirus, negatively regulates virus-induced type Ⅰ interferon response, apoptosis, and cell cycle arrest. Sci Rep, 2016, 6: 28354[2022-08-21]. .  DAI P, CAO H, MERGHOUB T, et al. Myxoma virus induces type Ⅰ interferon production in murine plasmacytoid dendritic cells via a TLR9/myd88-, IRF5/IRF7-, and IFNAR-dependent pathway. J Virol,2011,85(20): 10814–10825. doi:  O’NEILL L A, BOWIE A G. The family of five: TIR-domain-containing adaptors in toll-like receptor signalling. Nat Rev Immunol,2007,7(5): 353–364. doi:  LI Y G, SIRIPANYAPHINYO U, TUMKOSIT U, et al. Poly (i: C), an agonist of toll-like receptor-3, inhibits replication of the chikungunya virus in BEAS-2B cells. Virol J, 2012, 9: 114[2022-08-21]. .  LIN W, ZHANG J, LIN H, et al. Syndecan-4 negatively regulates antiviral signalling by mediating RIG-Ⅰ deubiquitination via CYLD. Nat Commun, 2016, 7: 11848[2022-08-21]. .  HEIDEGGER S, WINTGES A, STRITZKE F, et al. RIG-Ⅰ activation is critical for responsiveness to checkpoint blockade. Sci Immunol, 2019, 4(39): eaau8943[2022-08-21]. .  KARLSEN T A, BRINCHMANN J E. Liposome delivery of microRNA-145 to mesenchymal stem cells leads to immunological off-target effects mediated by RIG-Ⅰ. Mol Ther,2013,21(6): 1169–1181. doi:  YASUKAWA K, KOSHIBA T. Mitochondrial reactive zones in antiviral innate immunity. Biochim Biophys Acta Gen Subj, 2021, 1865(3): 129839[2022-08-21]. .  ZHANG Z D, XIONG T C, YAO S Q, et al. RNF115 plays dual roles in innate antiviral responses by catalyzing distinct ubiquitination of MAVs and MITA. Nat Commun, 2020, 11(1): 5536[2022-08-21]. .  HSU A C, DUA K, STARKEY M R, et al. MicroRNA-125a and -b inhibit a20 and MAVs to promote inflammation and impair antiviral response in COPD. JCI Insight, 2017, 2(7): e90443[2022-08-21]. .  YAN J, ZHANG Y, SU Y, et al. MicroRNA-125a targets MAVs and TRAF6 to modulate interferon signaling and promote HCV infection. Virus Res, 2021, 296: 198336[2022-08-21]. .  WAN S, ASHRAF U, YE J, et al. MicroRNA-22 negatively regulates poly(i: C)-triggered type Ⅰ interferon and inflammatory cytokine production via targeting mitochondrial antiviral signaling protein (MAVs). Oncotarget,2016,7(47): 76667–76683. doi:  HOU P, WANG H, ZHAO G, et al. MiR-3470b promotes bovine ephemeral fever virus replication via directly targeting mitochondrial antiviral signaling protein (MAVs) in baby hamster syrian kidney cells. BMC Microbiol, 2018, 18(1): 224[2022-08-21]. .  SUN L, WU J, DU F, et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type Ⅰ interferon pathway. Science,2013,339(6121): 786–791. doi:  SHEN A, ZHENG D, LUO Y, et al. MicroRNA-24-3p alleviates hepatic ischemia and reperfusion injury in mice through the repression of STING signaling. Biochem Biophys Res Commun,2020,522(1): 47–52. doi:  KHAN M, HARMS J S, LIU Y, et al. Brucella suppress STING expression via miR-24 to enhance infection. PLoS Pathog, 2020, 16(10): e1009020[2022-08-21]. .  SU H, ZHENG W, PAN J, et al. Circular RNA circSamd4a regulates antiviral immunity in teleost fish by upregulating STING through sponging miR-29a-3p. J Immunol,2021,207(11): 2770–2784. doi:  ZHOU Y, LI M, XUE Y, et al. Interferon-inducible cytoplasmic lncLrrc55-AS promotes antiviral innate responses by strengthening IRF3 phosphorylation. Cell Res,2019,29(8): 641–654. doi:  FAN J, CHENG M, CHI X, et al. A human long non-coding RNA lncATV promotes virus replication through restricting RIG-Ⅰ-mediated innate immunity. Front Immunol, 2019, 10: 1711[2022-08-21]. .  XIA P, WANG S, YE B, et al. A circular RNA protects dormant hematopoietic stem cells from DNA sensor cGAS-mediated exhaustion. Immunity, 2018, 48(4): 688−701.e687[2022-08-21]. .  WU Q, NING X, SUN L. Megalocytivirus induces complicated fish immune response at multiple RNA levels involving mRNA, miRNA, and circRNA. Int J Mol Sci, 2021, 22(6): 3156[2022-08-21]. .