Journal
JOURNAL OF VIROLOGY
Volume 96, Issue 12, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/jvi.00317-22
Keywords
3A; ANXA1; foot-and-mouth disease virus; interferons; viral replication
Categories
Funding
- National Key R&D Program of China [2021YFD1800300]
- National Natural Sciences Foundation of China [31602037, 31941002]
- Gansu Provincial Major project for science and technology development [21ZD3NA001]
- Technology Major Project of Gansu Province [21ZD3NA001]
- Chinese Academy of Agricultural Science and Technology Innovation Project [CAAS-ZDRW202006, CAAS-ASTIP-2022-LVRI]
- Development of Seneca virus vaccine project [LSY-2017-225]
- Basic Scientific Research Fund of CAAS [Y2019YJ07-1]
- LVRI [111610312020006]
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The present study reveals the regulatory roles of annexin-A1 (ANXA1) in RNA virus-induced interferon production and foot-and-mouth disease virus (FMDV) replication. ANXA1 positively regulates IFN-beta production through the TBK1-IRF3 axis and interacts with JAK1 and STAT1 to enhance signal transduction. FMDV 3A protein interacts with ANXA1 to inhibit its ability to promote IFN-beta production and suppress ANXA1-TBK1 complex formation, thereby modulating viral replication.
The RIG-I-like receptor signaling pathway is crucial for producing type I interferon (IFN-I) against RNA viruses. The present study observed that viral infection increased annexin-A1 (ANXA1) expression, and ANXA1 then promoted RNA virus-induced IFN-I production. Compared to ANXA1 wild-type cells, ANXA1(-/-) knockout cells showed IFN-beta production decreasing after viral stimulation. RNA virus stimulation induced ANXA1 to regulate IFN-beta production through the TBK1-IRF3 axis but not through the NF-kappa B axis. ANXA1 also interacted with JAK1 and STAT1 to increase signal transduction induced by IFN-beta or IFN-gamma. We assessed the effect of ANXA1 on the replication of foot-and-mouth disease virus (FMDV) and found that ANXA1 inhibits FMDV replication dependent on IFN-I production. FMDV 3A plays critical roles in viral replication and host range. The results showed that FMDV 3A interacts with ANXA1 to inhibit its ability to promote IFN-beta production. We also demonstrated that FMDV 3A inhibits the formation of ANXA1-TBK1 complex. These results indicate that ANXA1 positively regulates RNA virus-stimulated IFN-beta production and FMDV 3A antagonizes ANXA1-promoted IFN-beta production to modulate viral replication. IMPORTANCE FMDV is a pathogen that causes one of the world's most destructive and highly contagious animal diseases. The FMDV 3A protein plays a critical role in viral replication and host range. Although 3A is one of the viral proteins that influences FMDV virulence, its underlying mechanisms remain unclear. ANXA1 is involved in immune activation against pathogens. The present study demonstrated that FMDV increases ANXA1 expression, while ANXA1 inhibits FMDV replication. The results also showed that ANXA1 promotes RNA virus-induced IFN-I production through the IRF3 axis at VISA and TBK1 levels. ANXA1 was also found to interact with JAK1 and STAT1 to strengthen signal transduction induced by IFN-beta and IFN-gamma. 3A interacted with ANXA1 to inhibit ANXA1-TBK1 complex formation, thereby antagonizing the inhibitory effect of ANXA1 on FMDV replication. This study helps to elucidate the mechanism underlying the effect of the 3A protein on FMDV replication. FMDV is a pathogen that causes one of the world's most destructive and highly contagious animal diseases. The FMDV 3A protein plays a critical role in viral replication and host range.
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