2. Academic Validation
  3. SADS-CoV nsp1 inhibits the STAT1 phosphorylation by promoting K11/K48-linked polyubiquitination of JAK1 and blocks the STAT1 acetylation by degrading CBP

SADS-CoV nsp1 inhibits the STAT1 phosphorylation by promoting K11/K48-linked polyubiquitination of JAK1 and blocks the STAT1 acetylation by degrading CBP

  • J Biol Chem. 2024 Feb 21:105779. doi: 10.1016/j.jbc.2024.105779.
Yingjie Xiang 1,  Chunxiao Mou 2,  Liqi Zhu 1,  Ziyan Wang 1,  Kaichuang Shi 3,  Wenbin Bao 4,  Jiarui Li 1,  Xiang Chen 5,  Zhenhai Chen 6
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Yangzhou University, Yangzhou, China.
  • 2 College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, China; Jiangsu Key Laboratory of Zoonosis, Yangzhou University, China.
  • 3 Guangxi Center for Animal Disease Control and Prevention, Nanning, GX, China.
  • 4 Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, China.
  • 5 Jiangsu Key Laboratory of Zoonosis, Yangzhou University, China.
  • 6 College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, China. Electronic address: zhenhai@yzu.edu.cn.
PMID: 38395305 DOI: 10.1016/j.jbc.2024.105779
Abstract

The newly discovered zoonotic coronavirus swine acute diarrhea syndrome coronavirus (SADS-CoV) causes acute diarrhea, vomiting, dehydration, and high mortality rates in newborn piglets. Although SADS-CoV uses different strategies to evade the host's innate immune system, the specific mechanism(s) by which it blocks the interferon (IFN) response remains unidentified. In this study, the potential of SADS-CoV nonstructural proteins (nsp) to inhibit the IFN response was detected. The results determined that nsp1 was a potent antagonist of IFN response. SADS-CoV nsp1 efficiently inhibited signal transducer and activator of transcription 1 (STAT1) phosphorylation by inducing Janus kinase 1 (JAK1) degradation. Subsequent research revealed that nsp1 induced JAK1 polyubiquitination through K11 and K48 linkages, leading to JAK1 degradation via the ubiquitin-proteasome pathway. Furthermore, SADS-CoV nsp1 induced CREB-binding protein (CBP) degradation to inhibit IFN-stimulated gene (ISG) production and STAT1 acetylation, thereby inhibiting STAT1 dephosphorylation and blocking STAT1 transport out of the nucleus to receive Antiviral signaling. In summary, the results revealed the novel mechanisms by which SADS-CoV nsp1 blocks the JAK-STAT signaling pathway via the ubiquitin-proteasome pathway. This study yielded valuable findings on the specific mechanism of coronavirus nsp1 in inhibiting the JAK-STAT signaling pathway and the strategies of SADS-CoV in evading the host's innate immune system.

Keywords

Janus kinase 1; nonstructural protein 1; signal transducer and activator of transcription 1; swine acute diarrhea syndrome coronavirus; ubiquitination.

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  • HY-112951
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