PMID- 35319228 OWN - NLM STAT- MEDLINE DCOM- 20220415 LR - 20220924 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 96 IP - 7 DP - 2022 Apr 13 TI - GATA3 Inhibits Viral Infection by Promoting MicroRNA-155 Expression. PG - e0188821 LID - 10.1128/jvi.01888-21 [doi] LID - e01888-21 AB - Recognition of viral RNAs by melanoma differentiation associated gene-5 (MDA5) initiates chicken antiviral response by producing type I interferons. Our previous studies showed that chicken microRNA-155-5p (gga-miR-155-5p) enhanced IFN-beta expression and suppressed the replication of infectious burse disease virus (IBDV), a double-stranded RNA (dsRNA) virus causing infectious burse disease in chickens. However, the mechanism underlying IBDV-induced gga-miR-155-5p expression in host cells remains elusive. Here, we show that IBDV infection or poly(I:C) treatment of DF-1 cells markedly increased the expression of GATA-binding protein 3 (GATA3), a master regulator for TH2 cell differentiation, and that GATA3 promoted gga-miR-155-5p expression in IBDV-infected or poly(I:C)-treated cells by directly binding to its promoter. Surprisingly, ectopic expression of GATA3 significantly reduced IBDV replication in DF-1 cells, and this reduction could be completely abolished by treatment with gga-miR-155-5p inhibitors, whereas knockdown of GATA3 by RNA interference enhanced IBDV growth, and this enhancement could be blocked with gga-miR-155-5p mimics, indicating that GATA3 suppressed IBDV replication by gga-miR-155-5p. Furthermore, our data show that MDA5 is required for GATA3 expression in host cells with poly(I:C) treatment, so are the adaptor protein TBK1 and transcription factor IRF7, suggesting that induction of GATA3 expression in IBDV-infected cells relies on MDA5-TBK1-IRF7 signaling pathway. These results uncover a novel role for GATA3 as an antivirus transcription factor in innate immune response by promoting miR-155 expression, further our understandings of host response against pathogenic infection, and provide valuable clues to the development of antiviral reagents for public health. IMPORTANCE Gga-miR-155-5p acts as an important antivirus factor against IBDV infection, which causes a severe immunosuppressive disease in chicken. Elucidation of the mechanism regulating gga-miR-155-5p expression in IBDV-infected cells is essential to our understandings of the host response against pathogenic infection. This study shows that transcription factor GATA3 initiated gga-miR-155-5p expression in IBDV-infected cells by directly binding to its promoter, suppressing viral replication. Furthermore, induction of GATA3 expression was attributable to the recognition of dsRNA by MDA5, which initiates signal transduction via TBK1 and IRF7. Thus, it is clear that IBDV induces GATA3 expression via MDA5-TBK1-IRF7 signaling pathway, thereby suppressing IBDV replication by GATA3-mediated gga-miR-155-5p expression. This information remarkably expands our knowledge of the roles for GATA3 as an antivirus transcription factor in host innate immune response particularly at an RNA level and may prove valuable in the development of antiviral drugs for public health. FAU - Li, Jiaxin AU - Li J AD - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing, China. AD - College of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, Beijing, China. FAU - Haiyilati, Areayi AU - Haiyilati A AD - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing, China. AD - College of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, Beijing, China. FAU - Zhou, Linyi AU - Zhou L AD - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing, China. AD - College of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, Beijing, China. FAU - Chen, Juncheng AU - Chen J AD - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing, China. AD - College of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, Beijing, China. FAU - Wang, Yongqiang AU - Wang Y AD - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing, China. AD - College of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, Beijing, China. FAU - Gao, Li AU - Gao L AD - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing, China. AD - College of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, Beijing, China. FAU - Cao, Hong AU - Cao H AD - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing, China. AD - College of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, Beijing, China. FAU - Li, Xiaoqi AU - Li X AD - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing, China. AD - College of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, Beijing, China. FAU - Zheng, Shijun J AU - Zheng SJ AUID- ORCID: 0000-0002-6534-6737 AD - Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing, China. AD - College of Veterinary Medicine, China Agricultural Universitygrid.22935.3f, Beijing, China. LA - eng PT - Journal Article DEP - 20220323 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Antiviral Agents) RN - 0 (GATA3 Transcription Factor) RN - 0 (MicroRNAs) RN - O84C90HH2L (Poly I-C) SB - IM MH - Animals MH - Antiviral Agents MH - *Birnaviridae Infections/drug therapy/immunology/virology MH - Cell Line MH - Chickens MH - *GATA3 Transcription Factor/genetics MH - Gene Expression Regulation/drug effects/immunology MH - *Infectious bursal disease virus/physiology MH - *MicroRNAs/genetics/metabolism MH - Poly I-C/pharmacology MH - Virus Replication/physiology PMC - PMC9006930 OTO - NOTNLM OT - GATA3 OT - IBDV infection OT - miR-155 COIS- The authors declare no conflict of interest. EDAT- 2022/03/24 06:00 MHDA- 2022/04/16 06:00 PMCR- 2022/09/23 CRDT- 2022/03/23 12:13 PHST- 2022/03/24 06:00 [pubmed] PHST- 2022/04/16 06:00 [medline] PHST- 2022/03/23 12:13 [entrez] PHST- 2022/09/23 00:00 [pmc-release] AID - 01888-21 [pii] AID - jvi.01888-21 [pii] AID - 10.1128/jvi.01888-21 [doi] PST - ppublish SO - J Virol. 2022 Apr 13;96(7):e0188821. doi: 10.1128/jvi.01888-21. Epub 2022 Mar 23.