The long noncoding RNA MIR122HG is a precursor for miR-122-5p and negatively regulates the TAK1-induced innate immune response in teleost fish

Abstract

Long noncoding RNAs (lncRNAs) are a diverse subset of RNA species of noncoding transcripts that are usually longer than 200 nt. However, the biological role and function of many lncRNAs have not been fully identified. It has been shown that one potential function of lncRNAs is to act as a precursor miRNA and promote the production of multiple miRNAs. However, the function of the miiuy croaker lncRNA MIR122HG has not been explored. In the present study, we show that this differentially expressed teleost fish lncRNA can act as the host gene of miR-122-5p, regulate its expression, and indirectly regulate the expression of potential inflammatory target protein transforming growth factor-β–activated kinase 1. We show that MIR122HG can negatively regulate the transforming growth factor-β–activated kinase 1–triggered NF-κB and interferon regulatory factor 3 signaling pathways and subsequently attenuate the innate immune response. In addition, MIR122HG can promote the replication of Siniperca chuatsi rhabdovirus and exacerbate the pathological effects caused by viral infection. We conclude that the study of lncRNA–miRNA–mRNA interaction through bioinformatics analysis or experimental-supported analysis can provide information for further elucidation of the functions of fish lncRNAs in innate immunity. Long noncoding RNAs (lncRNAs) are a diverse subset of RNA species of noncoding transcripts that are usually longer than 200 nt. However, the biological role and function of many lncRNAs have not been fully identified. It has been shown that one potential function of lncRNAs is to act as a precursor miRNA and promote the production of multiple miRNAs. However, the function of the miiuy croaker lncRNA MIR122HG has not been explored. In the present study, we show that this differentially expressed teleost fish lncRNA can act as the host gene of miR-122-5p, regulate its expression, and indirectly regulate the expression of potential inflammatory target protein transforming growth factor-β–activated kinase 1. We show that MIR122HG can negatively regulate the transforming growth factor-β–activated kinase 1–triggered NF-κB and interferon regulatory factor 3 signaling pathways and subsequently attenuate the innate immune response. In addition, MIR122HG can promote the replication of Siniperca chuatsi rhabdovirus and exacerbate the pathological effects caused by viral infection. We conclude that the study of lncRNA–miRNA–mRNA interaction through bioinformatics analysis or experimental-supported analysis can provide information for further elucidation of the functions of fish lncRNAs in innate immunity. Pathogen infection of organisms induces a series of immune responses that naturally occur for the survival of the organism and the maintenance of immune homeostasis. In these processes, pattern recognition receptors (PRRs) are responsible for detecting pathogen-associated molecular patterns in the host immune system (1Hatinguais R. Willment J.A. Brown G.D. PAMPs of the fungal cell wall and mammalian PRRs.Curr. Top. Microbiol. Immunol. 2020; 425: 187-223PubMed Google Scholar, 2Zhou Y. He C. Wang L. Ge B. Post-translational regulation of antiviral innate signaling.Eur. J. Immunol. 2017; 47: 1414-1426Crossref PubMed Scopus (70) Google Scholar). PRRs mediate the activation of different downstream signaling pathways by recognizing the specific molecular characteristics of different pathogenic microorganisms. The activated signaling pathway induces immune response through the production of various inflammatory factors and type 1 interferons (IFN-1) to resist microbial infection or the entry of foreign objects. PRRs mainly include toll-like receptors (TLRs), retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs), nucleotide-binding oligomerization domain–containing protein–like receptors, C-type lectins, and some DNA sensors (3Aoshi T. Koyama S. Kobiyama K. Akira S. Ishii K.J. Innate and adaptive immune responses to viral infection and vaccination.Curr. Opin. Virol. 2011; 1: 226-232Crossref PubMed Scopus (100) Google Scholar). TLRs can recognize both extracellular and intracellular viruses, whereas RLRs are intracellular virus sensors, which are mainly responsible for identifying viral nucleic acid that invades the cytoplasm (4Creagh E.M. O'Neill L.A. 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Activated TRAF6 recruits the kinase receptor–interacting protein 1, which then interacts with the protein and activates the transforming growth factor-β–activated kinase 1 (TAK1) complex, activates NF- κB and mitogen-activated protein kinases (MAPKs), and induces inflammatory factors (7Kawasaki T. Kawai T. Toll-like receptor signaling pathways.Front. Immunol. 2014; 5: 461Crossref PubMed Scopus (1482) Google Scholar). TAK1 also plays an important role in the RLR pathway. After RIG-I recognizes the virus, crucial adaptor protein mitochondrial antiviral signaling protein is recruited, and then interferon regulatory factor 3 (IRF3) is activated by the IκB kinase complex, thus promoting the mass production of interferon-stimulating genes (ISGs) and IFN-1 (8Xu L.-G. Wang Y.-Y. Han K.-J. Li L.-Y. Zhai Z. Shu H.-B. VISA is an adapter protein required for virus-triggered IFN-β signaling.Mol. Cell. 2005; 19: 727-740Abstract Full Text Full Text PDF PubMed Scopus (1469) Google Scholar, 9Meylan E. 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It contains an N-terminal and C-terminal domain, and the C-terminal conformation changes to bind to TAK1-binding protein 1, which is a significant step in kinase activation and complex formation (10Sakurai H. Targeting of TAK1 in inflammatory disorders and cancer.Trends. Pharmacol. Sci. 2012; 33: 522-530Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). TAK1 plays a key role in innate immune pathway, and it can be modified through different ways to regulate the intensity of immune response, including phosphorylation (11Levin R.S. Hertz N.T. Burlingame A.L. Shokat K.M. Mukherjee S. Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: E4776-E4783Crossref PubMed Scopus (28) Google Scholar) and ubiquitination (12Zhang L. Chu Q. Chang R. Xu T. Inducible microRNA-217 inhibits NF-κB–and IRF3-driven immune responses in lower vertebrates through targeting TAK1.J. Immunol. 2020; 205: 1620-1632Crossref PubMed Scopus (22) Google Scholar). In mammals, several regulatory molecules regulate the of the innate immune response by kinase 1 inhibits NF- by Y. K. M. H. T. J. K. H. inhibits NF-κB through of Full Text Full Text PDF PubMed Scopus Google Scholar). interacts with TAK1, the of TAK1-binding protein 1 and with TAK1, and induces the activation of NF- κB and by the activation of IκB kinase and N-terminal kinase, E. negatively TAK1 in the toll-like receptor signaling Cell. 2014; 34: PubMed Scopus Google Scholar). In lower vertebrates as TAK1 antiviral signal the activation of host innate immunity S. Z. Chang H. J. Li J. J. H. antiviral signaling is differentially by and TRAF6 in Immunol. PubMed Scopus Google Scholar). In addition, miiuy croaker inhibits and antiviral innate immune responses by targeting the of TAK1 (12Zhang L. Chu Q. Chang R. Xu T. Inducible microRNA-217 inhibits NF-κB–and IRF3-driven immune responses in lower vertebrates through targeting TAK1.J. Immunol. 2020; 205: 1620-1632Crossref PubMed Scopus (22) Google Scholar). that TAK1 is a kinase that mediates innate immune response in the the regulatory of TAK1 antiviral pathway in fish be Long noncoding RNA which is a noncoding RNA is than 200 with and it of a acid and T. Chang Long noncoding RNA in and PubMed Scopus Google Scholar). is and lncRNA is in and other It is in and of the lncRNA of can be in other organisms Chu R. Long RNA regulation of and PubMed Scopus Google Scholar). The function of lncRNA biological of biological and It can not regulate cell and other also in the regulation of various pathological of the important functions of lncRNAs have been including as miRNA to and in protein C. of a noncoding RNA is in and regulation of PubMed Scopus Google Scholar, H. H. Li of RNA inhibits cell and by in cell J. 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Inducible microRNA-217 inhibits NF-κB–and IRF3-driven immune responses in lower vertebrates through targeting TAK1.J. Immunol. 2020; 205: 1620-1632Crossref PubMed Scopus (22) Google Scholar). the antiviral immunity is the and to resist virus production of inflammatory factors and of immune response can inflammatory or which is to the different of regulatory factors and are required to the maintenance of the immune homeostasis. the maintenance of immune is and by many biological a complex immune regulatory In this we that MIR122HG plays a regulatory role in teleost antiviral immunity. the expression of and the of MIR122HG inflammatory and We further that MIR122HG can the of and TAK1 as a target of The that both MIR122HG and NF- κB and signaling pathways by targeting TAK1, thus promoting replication can negatively regulate the antiviral immune response of miiuy croaker by targeting TAK1 (12Zhang L. Chu Q. Chang R. Xu T. Inducible microRNA-217 inhibits NF-κB–and IRF3-driven immune responses in lower vertebrates through targeting TAK1.J. Immunol. 2020; 205: 1620-1632Crossref PubMed Scopus (22) Google Scholar). The regulation of TAK1 by and is both and miRNA can regulate the of by its with the of whereas the of and are However, the regulation of TAK1 by the two is with other the two a role through different on the of The two we and TAK1 both an important regulatory role it that the two can regulate TAK1 miRNA is a of regulatory molecules that and has conserved The important regulatory functions of are than is in various as and in inhibits the and of by targeting in L. Z. Z. T. J. H. M. L. Y. the and of by targeting 2020; Scopus Google Scholar). In can target kinase as a promoting cell and S. A. D. M. cell and of by negatively PubMed Scopus Google Scholar). In the of by targeting Wang the of by cell PubMed Scopus (22) Google Scholar). inhibits protein 3 through MAPK signaling in to promote and in Z. Wang and in by protein 3 through mitogen-activated protein kinase 2020; PubMed Scopus Google Scholar). plays a regulatory role in various a have its on the innate immunity of viral The present study that fish also can the antiviral immune response, indicating its important role in immune that the innate immunity of teleost fish is an important of the innate immunity of the regulatory factors and regulatory of teleost fish be the role of lncRNA as a of different biological in and vertebrates has been The of RNA is one of the that lncRNA the of by in fish and that lncRNA Q. Xu T. Chang R. L. Long noncoding RNA innate antiviral responses by in teleost Sci. 2020; Google lncRNA Q. Xu T. Chang R. L. Long noncoding RNA antiviral responses through in lower 2020; Scopus Google and Chu Q. Xu T. Long noncoding RNA immune responses through of in teleost Full Text Full Text PDF PubMed Scopus Google Scholar) act as molecular to bind and the caused by miRNA of the immune response. In addition, lncRNA can be as the host gene of miRNA to regulate the production of miRNA to indirectly regulate in which has a expression is by the gene whereas is target the of Y. Q. Li C. R. Z. B. Wang J. H. lncRNA and mediate 2017; PubMed Scopus Google Scholar). lncRNA through and is an molecule of the which a for the of through a Wang Y. T. E. Q. T. K. Wang inhibits in 2017; 19: PubMed Scopus Google Scholar). The the to a miRNA lncRNA is that this of lncRNA that can miRNA can mediate the of through in of this lncRNA not the pathway to thus that in lncRNA transcripts is not important A. S. mediates of noncoding RNA transcripts PubMed Scopus Google Scholar). In the present study, we that fish lncRNA MIR122HG can for the We it the and this innate immune response. We that the expression viral infection and could negatively regulate the antiviral immunity by TAK1 and inhibits the of MIR122HG the expression of as an important the of immunity and plays an important role in fish antiviral immunity. In the present study, we a lncRNA MIR122HG in miiuy croaker and that it can negatively regulate the antiviral immune response. we that can negatively regulate NF- κB and signaling that MIR122HG can by as a precursor of and then indirectly the antiviral immune response. MIR122HG could be in antiviral immunity. In addition, the inflammatory and by the of provide the negatively regulation of antiviral innate response in fish by lncRNA and the on the croaker in for 6 for as Chu Q. L. L. Xu T. RNA antiviral immune responses through of in teleost Scopus Google Scholar). in with the of for the and of and the by the of M. miiuy M. miiuy and M. miiuy in with and Chu Q. L. L. Xu T. RNA antiviral immune responses through of in teleost Scopus Google Scholar). in with and in Chu Q. L. L. Xu T. RNA antiviral immune responses through of in teleost Scopus Google Scholar). in modified which the and and with R. Xu T. and regulate NF-κB signaling by targeting in teleost Immunol. 2020; PubMed Scopus Google Scholar). and with a of infection of and different for RNA Chu Q. L. L. Xu T. RNA antiviral immune responses through of in teleost Scopus Google Scholar). the TAK1 the of miiuy croaker TAK1 gene as as L. and TAK1 and MIR122HG expression the of MIR122HG in species or with The with in the with specific miiuy croaker TAK1 gene the which the of the TAK1 expression as (12Zhang L. Chu Q. Chang R. Xu T. Inducible microRNA-217 inhibits NF-κB–and IRF3-driven immune responses in lower vertebrates through targeting TAK1.J. Immunol. 2020; 205: 1620-1632Crossref PubMed Scopus (22) Google Scholar). The of the by and through DNA The potential downstream of the of the of mammalian Full Text Full Text PDF PubMed Scopus Google B. A. T. C. PubMed Scopus Google and M. A for of miRNA in an RNA 2005; 33: PubMed Scopus Google Scholar). The to the of targeting as by the and of the of MIR122HG the different species The are with naturally miRNAs. The The miRNA are that intracellular and their in the pathway. The The the and are as and of with miRNA miRNA or in and with DNA to the the or and miRNA miRNA or in and then for further miRNA or miRNA and the or of miRNA target or MIR122HG or with TAK1 or TAK1 the of a system the regulation of miR-122-5p, with NF- or gene TAK1 expression and with MIR122HG expression or the for the the of in in of to for and RNA with and the DNA the which of RNA to The expression patterns of gene by The RNA by miRNA and miRNA to of miRNAs. The expression analysis of by the miRNA in an 3 and as for and The interaction of TAK1 and NF-κB activation Immunol. 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