Porcine deltacoronavirus nucleocapsid protein antagonizes JAK-STAT signaling pathway by targeting STAT1 through KPNA2 degradation.

Publication date: Jul 23, 2024

Porcine deltacoronavirus (PDCoV) is an enteric pathogenic coronavirus that causes acute and severe watery diarrhea in piglets and has the ability of cross-species transmission, posing a great threat to swine production and public health. The interferon (IFN)-mediated signal transduction represents an important component of virus-host interactions and plays an essential role in regulating viral infection. Previous studies have suggested that multifunctional viral proteins encoded by coronaviruses antagonize the production of IFN via various means. However, the function of these viral proteins in regulating IFN-mediated signaling pathways is largely unknown. In this study, we demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I IFN-mediated JAK-STAT signaling pathway. We identified that PDCoV infection stimulated but delayed the production of IFN-stimulated genes (ISGs). In addition, PDCoV inhibited JAK-STAT signal transduction by targeting the nuclear translocation of STAT1 and ISGF3 formation. Further evidence showed that PDCoV N is the essential protein involved in the inhibition of type I IFN signaling by targeting STAT1 nuclear translocation via its C-terminal domain. Mechanistically, PDCoV N targets STAT1 by interacting with it and subsequently inhibiting its nuclear translocation. Furthermore, PDCoV N inhibits STAT1 nuclear translocation by specifically targeting KPNA2 degradation through the lysosomal pathway, thereby inhibiting the activation of downstream sensors in the JAK-STAT signaling pathway. Taken together, our results reveal a novel mechanism by which PDCoV N interferes with the host antiviral response. IMPORTANCEPorcine deltacoronavirus (PDCoV) is a novel enteropathogenic coronavirus that receives increased attention and seriously threatens the pig industry and public health. Understanding the underlying mechanism of PDCoV evading the host defense during infection is essential for developing targeted drugs and effective vaccines against PDCoV. This study demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I interferon signaling by targeting STAT1, which is a crucial signal sensor in the JAK-STAT signaling pathway. Further experiments suggested that PDCoV N-mediated inhibition of the STAT1 nuclear translocation involves the degradation of KPNA2, and the lysosome plays a role in KPNA2 degradation. This study provides new insights into the regulation of PDCoV N in the JAK-STAT signaling pathway and reveals a novel mechanism by which PDCoV evades the host antiviral response. The novel findings may guide us to discover new therapeutic targets and develop live attenuated vaccines for PDCoV infection.

Concepts Keywords
Antagonizes alpha Karyopherins
Coronaviruses alpha Karyopherins
Enteropathogenic Animals
Genes Cell Line
Live Coronavirus Infections
Deltacoronavirus
HEK293 Cells
Host-Pathogen Interactions
Humans
immune escape
Interferon Type I
Interferon Type I
JAK-STAT signal pathway
Janus Kinases
Janus Kinases
KPNA2
nucleocapsid protein
Nucleocapsid Proteins
Nucleocapsid Proteins
porcine deltacoronavirus (PDCoV)
Proteolysis
Signal Transduction
STAT1
STAT1 Transcription Factor
STAT1 Transcription Factor
Swine
Swine Diseases

Semantics

Type Source Name
pathway KEGG JAK-STAT signaling pathway
disease MESH causes
disease IDO production
pathway REACTOME Signal Transduction
disease IDO host
disease MESH viral infection
disease MESH infection
disease VO effective
pathway KEGG Lysosome
disease IDO cell
disease MESH Coronavirus Infections
disease IDO pathogen
disease MESH Swine Diseases

Original Article

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