DYRK1A is a multifunctional host factor that regulates coronavirus replication in a kinase-independent manner
Zhen Fu, Yixin Xiang, Yanan Fu, Zhelin Su, Yubei Tan, Mengfang Yang, Yuanyuan Yan, Hakimeh Baghaei Daemi, Yuejun Shi, Shengsong Xie, Limeng Sun, Guiqing Peng
Journal of Virology, doi:10.1128/jvi.01239-23
Coronaviruses (CoVs) pose a major threat to human and animal health worldwide, which complete viral replication by hijacking host factors. Identifying host factors essential for the viral life cycle can deepen our understanding of the mechanisms of virus-host interactions. Based on our previous genome-wide CRISPR screen of α-CoV transmissible gastroenteritis virus (TGEV), we identified the host factor dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), but not DYRK1B, as a critical factor in TGEV replication. Rescue assays and kinase inhibitor experiments revealed that the effect of DYRK1A on viral replication is independent of its kinase activity. Nuclear localization signal modification experiments showed that nuclear DYRK1A facilitated virus replication. Furthermore, DYRK1A knockout significantly downregulated the expression of the TGEV receptor aminopeptidase N (ANPEP) and inhibited viral entry. Notably, we also demonstrated that DYRK1A is essential for the early stage of TGEV replication. Transmission electron microscopy results indicated that DYRK1A contributes to the formation of double-membrane vesicles in a kinase-independent manner. Finally, we validated that DYRK1A is also a proviral factor for mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. In conclusion, our work demonstrated that DYRK1A is an essential host factor for the replication of multiple viruses, providing new insights into the mechanism of virus-host interactions and facilitating the development of new broad-spectrum antiviral drugs. IMPORTANCE Coronaviruses, like other positive-sense RNA viruses, can remodel the host membrane to form double-membrane vesicles (DMVs) as their replication organelles. Currently, host factors involved in DMV formation are not well defined. In this study, we used transmissible gastroenteritis virus (TGEV) as a virus model to investigate the regulatory mechanism of dual-specificity tyrosine phosphorylation-regu lated kinase 1A (DYRK1A) on coronavirus. Results showed that DYRK1A significantly inhibited TGEV replication in a kinase-independent manner. DYRK1A knockout (KO) can regulate the expression of receptor aminopeptidase N (ANPEP) and endocytic-related genes to inhibit virus entry. More importantly, our results revealed that DYRK1A KO notably inhibited the formation of DMV to regulate the virus replication. Further data proved that DYRK1A is also essential in the replication of mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. Taken together, our findings demonstrated that DYRK1A is a conserved factor for positive-sense RNA viruses and provided new insights into its transcriptional regulation activity, revealing its potential as a candidate target for therapeutic design.
Confocal microscopy To observe the endocytosis of the TGEV in host cells, the same amount of DYRK1A KO cells and control cells were cultured in 35 mm Petri dishes overnight. An equivalent dose of TGEV (MOI = 5) was added to each well and incubated at 4°C for 60 minutes for complete adsorption and then transferred to 37°C and incubated for 30 minutes for endocytosis. Immunofluorescence assays were performed as described above, while the images were acquired using a laser scanning confocal microscope (Nikon). The subcellular localization of DYRK1A in DYRK1A KO cells and control cells transfected with DYRK1A-FLAG-pcDNA3.1 plasmid was observed after 24 h. Afterward, TGEV (MOI = 1) was added into these cells, incubated for 24 h, immunolabeled with a FLAG-tag antibody (Proteintech, no. 20543-1-AP; MBL, no. PM020) and dsRNA antibody (SCICONS, no. 10010200, 1:1,000), and imaged to identify double-fluorescent positive cells.
Statistical analysis Statistical significance values were assessed using GraphPad Prism 8.0. Two-tailed unpaired t-tests were used for data analysis. Unless otherwise stated, the data represent the mean ± standard deviation of experiments performed, at least, in triplicate.
AUTHOR AFFILIATIONS
ADDITIONAL FILES The following material is available online.
Supplemental Material Supplemental figures (JVI01239-23-s0001.docx). Fig. S1 and S2 .
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"abstract": "<jats:title>ABSTRACT</jats:title>\n <jats:p>\n Coronaviruses (CoVs) pose a major threat to human and animal health worldwide, which complete viral replication by hijacking host factors. Identifying host factors essential for the viral life cycle can deepen our understanding of the mechanisms of virus–host interactions. Based on our previous genome-wide CRISPR screen of α-CoV transmissible gastroenteritis virus (TGEV), we identified the host factor dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), but not DYRK1B, as a critical factor in TGEV replication. Rescue assays and kinase inhibitor experiments revealed that the effect of DYRK1A on viral replication is independent of its kinase activity. Nuclear localization signal modification experiments showed that nuclear DYRK1A facilitated virus replication. Furthermore, DYRK1A knockout significantly downregulated the expression of the TGEV receptor aminopeptidase N (\n <jats:italic>ANPEP</jats:italic>\n ) and inhibited viral entry. Notably, we also demonstrated that DYRK1A is essential for the early stage of TGEV replication. Transmission electron microscopy results indicated that DYRK1A contributes to the formation of double-membrane vesicles in a kinase-independent manner. Finally, we validated that DYRK1A is also a proviral factor for mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. In conclusion, our work demonstrated that DYRK1A is an essential host factor for the replication of multiple viruses, providing new insights into the mechanism of virus–host interactions and facilitating the development of new broad-spectrum antiviral drugs.\n </jats:p>\n <jats:sec>\n <jats:title>IMPORTANCE</jats:title>\n <jats:p>\n Coronaviruses, like other positive-sense RNA viruses, can remodel the host membrane to form double-membrane vesicles (DMVs) as their replication organelles. Currently, host factors involved in DMV formation are not well defined. In this study, we used transmissible gastroenteritis virus (TGEV) as a virus model to investigate the regulatory mechanism of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) on coronavirus. Results showed that DYRK1A significantly inhibited TGEV replication in a kinase-independent manner. DYRK1A knockout (KO) can regulate the expression of receptor aminopeptidase N (\n <jats:italic>ANPEP</jats:italic>\n ) and endocytic-related genes to inhibit virus entry. More importantly, our results revealed that DYRK1A KO notably inhibited the formation of DMV to regulate the virus replication. Further data proved that DYRK1A is also essential in the replication of mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. Taken together, our findings demonstrated that DYRK1A is a conserved factor for positive-sense RNA viruses and provided new insights into its transcriptional regulation activity, revealing its potential as a candidate target for therapeutic design.\n </jats:p>\n </jats:sec>",
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