The circular RNA circBCL2L1 regulates innate immune responses via microRNA-mediated downregulation of TRAF6 in teleost fish

Abstract

Growing numbers of studies have shown that circular RNAs (circRNAs) can function as regulatory factors to regulate the innate immune response, cell proliferation, cell migration, and other important processes in mammals. However, the function and regulatory mechanism of circRNAs in lower vertebrates are still unclear. Here, we discovered a novel circRNA derived from the gene encoding Bcl-2-like protein 1 (BCL2L1) gene, named circBCL2L1, which was related to the innate immune responses in teleost fish. Results indicated that circBCL2L1 played essential roles in host antiviral immunity and antibacterial immunity. Our study also identified a microRNA, miR-30c-3-3p, which could inhibit the innate immune response by targeting inflammatory mediator TRAF6. And TRAF6 is a key signal transduction factor in innate immune response mediated by TLRs. Moreover, we also found that the antiviral and antibacterial effects inhibited by miR-30c-3-3p could be reversed with the expression of circBCL2L1. Our data revealed that circBCL2L1 functioned as a competing endogenous RNA (ceRNA) of TRAF6 by competing for binding with miR-30c-3-3p, leading to activation of the NF-κB/IRF3 inflammatory pathway and then enhancing the innate immune responses. Our results suggest that circRNAs can play an important role in the innate immune response of teleost fish. Growing numbers of studies have shown that circular RNAs (circRNAs) can function as regulatory factors to regulate the innate immune response, cell proliferation, cell migration, and other important processes in mammals. However, the function and regulatory mechanism of circRNAs in lower vertebrates are still unclear. Here, we discovered a novel circRNA derived from the gene encoding Bcl-2-like protein 1 (BCL2L1) gene, named circBCL2L1, which was related to the innate immune responses in teleost fish. Results indicated that circBCL2L1 played essential roles in host antiviral immunity and antibacterial immunity. Our study also identified a microRNA, miR-30c-3-3p, which could inhibit the innate immune response by targeting inflammatory mediator TRAF6. And TRAF6 is a key signal transduction factor in innate immune response mediated by TLRs. Moreover, we also found that the antiviral and antibacterial effects inhibited by miR-30c-3-3p could be reversed with the expression of circBCL2L1. Our data revealed that circBCL2L1 functioned as a competing endogenous RNA (ceRNA) of TRAF6 by competing for binding with miR-30c-3-3p, leading to activation of the NF-κB/IRF3 inflammatory pathway and then enhancing the innate immune responses. Our results suggest that circRNAs can play an important role in the innate immune response of teleost fish. As the first line of defense against foreign pathogens, the innate immune system mainly relies on various pattern recognition receptors (PRRs) to quickly recognize various pathogen-associated molecular patterns (PAMPs) carried by foreign pathogens and quickly transmit the signal to the key downstream adapter proteins to activate various host immune responses (1Baccala R. Kono D.H. Theofilopoulos A.N. Interferons as pathogenic effectors in autoimmunity.Immunol. Rev. 2005; 204: 9-26Crossref PubMed Scopus (166) Google Scholar). This process can make the host cells produce type I interferon, inflammatory factors, or chemokines in time to remove the invading host pathogens, so as to protect the host from the invasion of pathogenic microorganisms (2Akira S. Uematsu S. Takeuchi O. Pathogen recognition and innate immunity.Cell. 2006; 124: 783-801Abstract Full Text Full Text PDF PubMed Scopus (8426) Google Scholar). 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The expression of TRAF6 so is important for TRAF6. In the of a of regulatory factors of TRAF6 in mammals. For example, can inhibit the of by targeting TRAF6 C. Y. Y. J. The role of in Rev. 21: Google Scholar). Moreover, found that can host response to virus by targeting signal M. A. the host response to virus by targeting the signaling PubMed Scopus Google Scholar). In to the that can regulate TRAF6 in have found a of that can regulate the and signaling pathway in have found that and can as of TRAF6 to regulate mediated immune response and the immune response of the Y. T. signaling pathway targeting TRAF6 in Immunol. 113: PubMed Scopus Google Scholar, R. Y. T. the and pathway in teleost by targeting Immunol. PubMed Scopus Google Scholar). the of TRAF6 in we still the role of TRAF6 in innate immune response in lower as teleost of the regulatory mechanism of signal transduction is As a of the function and of circular RNAs (circRNAs) in are Unlike other circRNA is a circular molecule by and is first found in the virus in the are circular RNA molecules as S. A. PubMed Scopus Google Scholar). circRNA was as a of with the of that circRNA is a important regulatory which an role in the process of and so on J. C. RNAs are the from of in cell PubMed Scopus Google Scholar, J. specific of circular RNA PubMed Scopus Google Scholar, J. RNA potential and Full Text Full Text PDF PubMed Scopus Google Scholar). to circRNA to play mainly in binding to protein in protein and can act as of to as competing endogenous RNAs J. RNA function as PubMed Scopus Google Scholar, circular RNA cell with and PubMed Scopus Google Scholar, M. K. Y. S. H. J. H. A by circular form of in PubMed Scopus Google Scholar). Moreover, a of studies have that circRNA can act as a to in antiviral immune For example, virus by to regulate in S. Y. M. M. A virus by to regulate PubMed Scopus Google Scholar). In studies have shown that circRNA can antiviral signaling pathway by targeting in teleost T. RNA antiviral immune responses through of TRIF in teleost PubMed Scopus Google Scholar). that circRNA can regulate antiviral related immune through the mechanism in lower is circRNA can regulate antibacterial immune response by as in lower In we a regulatory in innate immune response in teleost Our studies have the important role of TRAF6 in antiviral and antibacterial immune responses. Here, we have found that miR-30c-3-3p TRAF6 and innate immune responses. study that a circular circBCL2L1, can as a for miR-30c-3-3p to TRAF6 innate responses. Our results the mechanism of in innate immune response, also for the study of innate immune in lower In a of circRNAs have found to in the antiviral immune response K. M. H. T. between and in PubMed Scopus Google Scholar), is the role of circRNAs in immune response in lower the expression of circRNA with data and found that the expression of circBCL2L1 was H. R. T. A circular RNA antiviral immunity by the pathway in lower Scopus Google Scholar). with and to the of to and then the expression of circBCL2L1 by In that circRNAs by RNA the expression of Bcl-2-like protein 1 (BCL2L1) and circBCL2L1 also The results that circBCL2L1 was and with In cells the expression of circBCL2L1 then the expression of circBCL2L1 in and cells the cell and cells the and the expression of circBCL2L1, we and to the function and regulatory mechanism of circBCL2L1. the gene with the of the T. R. R. Y. J. S. C. Y. T. The of the innate immune and PubMed Scopus Google Scholar, T. Y. A of the and found that the gene was on circBCL2L1 was of the of with a of circRNAs to the is the of or the first to circBCL2L1, and the of the in the of circBCL2L1 we to gene and to circBCL2L1. and from and and to and The results shown in indicated that circBCL2L1 was from by and we the of in was from that was a of we to the of circBCL2L1. 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The results that of circBCL2L1 the of cells of circBCL2L1, that circBCL2L1 the of cell This that the circBCL2L1 can regulate the antiviral responses and the expression of inflammatory and antiviral the of the virus to cells and cell Moreover, as a process of healthy cell can the of we can the of cells from the of cell we the of circBCL2L1 on the cell of we found that of circBCL2L1 cell with the of In these data that circBCL2L1, as a is in the of innate and the data of the cell and that the circBCL2L1 can regulate the antiviral responses and the expression of inflammatory and antiviral the of the pathogen to cells and cell and cell the of circBCL2L1 to to to circBCL2L1 can function as a we or cells to RNA for The results that endogenous circBCL2L1 could be by that circBCL2L1 have a binding with to with circBCL2L1, we first and for and for and we the expression of these in cells with or and cells with or the miR-30c-3-3p expression was circBCL2L1 was miR-30c-3-3p expression was in response to circBCL2L1 with other the miR-30c-3-3p to circBCL2L1 the of miR-30c-3-3p and the binding of miR-30c-3-3p and circBCL2L1. we the miR-30c-3-3p with miR-30c-3-3p, or circBCL2L1 The by miR-30c-3-3p was with circBCL2L1 that circBCL2L1 miR-30c-3-3p, from circBCL2L1 could regulate miR-30c-3-3p expression and and circBCL2L1 function as a of the of circBCL2L1 to circBCL2L1 could with miR-30c-3-3p and found that circBCL2L1 a binding of miR-30c-3-3p we a of circBCL2L1 and the form of miR-30c-3-3p binding revealed that miR-30c-3-3p could the of the form of circBCL2L1 on the form In miR-30c-3-3p inhibited in and and Moreover, we a or a form of circBCL2L1 the and with miR-30c-3-3p could the of protein As shown in and the results revealed that miR-30c-3-3p could inhibit the of which that a between circBCL2L1 and that gene expression by binding to we the of circBCL2L1 to to in cells by miR-30c-3-3p, and The results from indicated that circBCL2L1 and miR-30c-3-3p by RNA with circBCL2L1 or miR-30c-3-3p to the between circBCL2L1 and The results from the revealed that miR-30c-3-3p could be by circBCL2L1 miR-30c-3-3p circBCL2L1 with the and to the between circBCL2L1 and an and to that could produce circBCL2L1 identified by the also a and gene expression to produce a protein that could with the and be identified an that with circBCL2L1 could be by the The results from that the was for miR-30c-3-3p with or these data that circBCL2L1 could to miR-30c-3-3p, and circBCL2L1 as a of could regulate the expression of by binding to we the potential of miR-30c-3-3p the innate gene which we are in we TRAF6 as a gene of miR-30c-3-3p for first the of TRAF6 and found that miR-30c-3-3p a with TRAF6 the and the of TRAF6 and then with miR-30c-3-3p or to the between miR-30c-3-3p and TRAF6. 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The indicated that the miR-30c-3-3p can regulate the antiviral responses and the expression of inflammatory and antiviral the of virus to cells and cell that circBCL2L1 could with miR-30c-3-3p and miR-30c-3-3p TRAF6 and we circBCL2L1 could regulate TRAF6. As shown in of circBCL2L1 the expression of TRAF6 while of circBCL2L1 the protein of TRAF6. 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In of the important role of TRAF6 mediated signaling pathway in innate immune response, that can regulate immune related be an and important in the Growing of studies have shown that circRNAs can be as to regulate For example, the circRNA cell proliferation, migration, and invasion through pathway pathway to inhibit PubMed Scopus Google Scholar). Moreover, a novel identified circular by targeting A novel identified circular by targeting PubMed Scopus Google Scholar). the of by to expression Y. Y. J. the of by to Scopus Google Scholar). a of studies have on the function of circRNA through mechanism in are in lower in teleost fish. Here, we that a circRNA circBCL2L1, which was and can TRAF6 expression through miR-30c-3-3p in lower found that the expression of circBCL2L1 through the of or and we that be the circBCL2L1 a important role in innate and to the innate immune response by or results that circRNAs are in the of immune response as a immune regulatory molecule in lower In we found a novel circBCL2L1, which was in the of innate antiviral immune responses in teleost fish. miR-30c-3-3p was also a discovered that could regulate innate immune responses. the circBCL2L1 played a role in innate immune responses. that the mechanism of the played a role in the innate immune responses. circBCL2L1 could be as the of miR-30c-3-3p to on TRAF6 the of the In we also found that the and function of circBCL2L1 in teleost fish. In study revealed that circRNA is in the host pathogen mechanism and the important role of circRNA in innate immunity. in with the of for the and of and the by the of was from was in for and as T. R. 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