2. Academic Validation
  3. Classical swine fever virus NS5A protein antagonizes innate immune response by inhibiting the NF-κB signaling

Classical swine fever virus NS5A protein antagonizes innate immune response by inhibiting the NF-κB signaling

  • Virol Sin. 2023 Sep 13;S1995-820X(23)00110-4. doi: 10.1016/j.virs.2023.09.002.
Jinfu Sun 1,  Jiaying Li 2,  Liming Li 2,  Haixiao Yu 2,  Ping Ma 2,  Yingnan Wang 2,  Jinqi Zhu 2,  Zezhong Feng 2,  Changchun Tu 3
Affiliations

Affiliations

  • 1 Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China. Electronic address: sunjinfu@mail.neu.edu.cn.
  • 2 Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China.
  • 3 Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, 225009, China. Electronic address: changchun_tu@hotmail.com.
PMID: 37714433 DOI: 10.1016/j.virs.2023.09.002
Abstract

The NS5A non-structural protein of classical swine fever virus (CSFV) is a multifunctional protein involved in viral genomic replication, protein translation, assembly of infectious virus particles, and regulation of cellular signaling pathways. Previous report showed that NS5A inhibited nuclear factor kappa B (NF-κB) signaling induced by poly(I:C); however, the mechanism involved has not been elucidated. Here, we reported that NS5A directly interacted with NF-κB essential modulator (NEMO), a regulatory subunit of the IκB kinase (IKK) complex, to inhibit the NF-κB signaling pathway. Further investigations showed that the zinc finger domain of NEMO and the aa 126-250 segment of NS5A are essential for the interaction between NEMO and NS5A. Mechanistic analysis revealed that NS5A mediated the proteasomal degradation of NEMO. Ubiquitination assay showed that NS5A induced the K27-linked but not the K48-linked polyubiquitination of NEMO for proteasomal degradation. In addition, NS5A blocked the K63-linked polyubiquitination of NEMO, thus inhibiting IKK phosphorylation, IκBα degradation, and NF-κB activation. These findings revealed a novel mechanism by which CSFV inhibits host innate immunity, which might guide the drug design against CSFV in the future.

Keywords

Classical swine fever virus (CSFV); NEMO; NF-κB signaling; NS5A; polyubiquitination; proteasomal degradation.

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