Abstract
Viruses have evolved many mechanisms to escape host antiviral responses. Previously, we found that classical swine fever virus (CSFV) infection induces autophagy using the autophagosome as a self-replication site, thereby evading the host immune response and promoting long-term infection. However, the underlying mechanisms used by CSFV to enter autophagosomes and the mechanism by which autophagy promotes viral replication remain unclear. We found that CSFV infection inhibited autophagy receptor nuclear dot protein 52 kDa (NDP52) expression, ubiquitination, and SUMO2-4 modification. Further analyses revealed that CSFV mediated ubiquitination and SUMOylation of NDP52 via Pten-induced kinase 1 (PINK1)-Parkin. Moreover, NDP52 inhibition also inhibited CSFV replication and the induction of mitophagy marker proteins expression. Inhibition of NDP52 reduced CD63 expression and binding to CSFV E2 protein, which has an essential role in persistent CSFV infection. As NDP52 has a close relationship with the NF-κB innate immunity pathway and plays an important role in the antiviral response, we investigated whether NDP52 inhibited CSFV replication through the release of immune factors and antivirus signals. Our results showed that inhibiting NDP52 boosted interferon and TNF release and promoted NF-κB pathway activation. In summary, we found that NDP52 inhibition not only reduces CSFV binding and entry into autophagic vesicles, but also inhibits CSFV replication by active NF-κB antiviral immune pathways. Our data reveal a novel mechanism by which NDP52, an autophagy receptor, mediates CSFV infection, and provide new avenues for the development of antiviral strategies.
Highlights
Swine fever, caused by classical swine fever virus (CSFV) infection, is characterized by acute fever and death, and is classified as a Class A infectious disease by the World Organization for Animal Health (OIE) (Paton and Greiser-Wilke, 2003)
These results suggest that CSFV infection has a negative effect on the expression of nuclear dot protein 52 kDa (NDP52)
These results showed that NDP52 ubiquitination and SUMOylation were decreased in CSFV-infected cells compared to that in uninfected PK-15 cells (Figures 1C,D)
Summary
Swine fever, caused by classical swine fever virus (CSFV) infection, is characterized by acute fever and death, and is classified as a Class A infectious disease by the World Organization for Animal Health (OIE) (Paton and Greiser-Wilke, 2003). The most important feature of the selective autophagy pathway is the involvement of autophagy receptors that recognize and transport autophagic substrates, thereby regulating autophagy substrate degradation under very precise dynamic control (Lazarou et al, 2015) These autophagy receptors contain a conserved LC3-interacting region (LIR) domain, which binds to Atg molecules on autophagosomes and mediate autophagy degradation (Zaffagnini and Martens, 2016). In CVB virus infection, CALCOCO2, but not SQSTM1, suppresses antiviral type I IFN signaling by promoting autophagy-mediated degradation of the mitochondrial antiviral signaling (MAVS) protein (Mohamud et al, 2018). We sought to explore the regulatory effect of NDP52 on NF-κB and IFN in swine fever virus infection and hypothesized that it plays an important role in CSFV infection. NDP52 colocalizes with viral protein E2, thereby inhibiting CD63 expression, promoting CSFV binding by NDP52 and increasing cytokine release and NF-κB signaling activation
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