Type I unconventional protein secretion of the SARS-CoV-2 nucleocapsid protein promotes inflammatory cytokine release

  • Cell Rep. 2026 Jun 25;45(7):117613. doi: 10.1016/j.celrep.2026.117613.
Liwei Zheng  1 ,  Minghui Li  1 ,  Weilin Gu  1 ,  Jing Zhao  2 ,  Bei Jiang  3 ,  Qianqian Jiang  4 ,  Kun Liu  5 ,  Yu Guo  6 ,  Ran Xu  5 ,  Xin Liu  1 ,  Ting Zhang  1 ,  Danli Yang  1 ,  Sidi Yang  7 ,  Lihong Liu  7 ,  Qingquan Liu  8 ,  Lin Wang  9 ,  Sujun Zheng  10 ,  Fengmin Lu  11 ,  Xiangmei Chen  12
Affiliations
  • 1. Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 2. First Department of Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
  • 3. Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China; Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China.
  • 4. Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China.
  • 5. Research & Development Department, Shenzhen New Industries Biomedical Engineering Co., Ltd., Shenzhen, P.R. China.
  • 6. Tianjin Hospital of ITCMW Nankai Hospital, Tianjin, China.
  • 7. Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China.
  • 8. Beijing Hospital of Traditional Chinese Medicine, Beijing, China. Electronic address: [email protected].
  • 9. Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China. Electronic address: [email protected].
  • 10. First Department of Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China. Electronic address: [email protected].
  • 11. Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 12. Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: [email protected].
PMID: 42360880 DOI: 10.1016/j.celrep.2026.117613
Abstract

SARS-CoV-2 Infection remains a global health threat, yet its pathogenic mechanisms are incompletely understood. Here, we show that viral nucleocapsid protein (NP) is detectable in the serum of patients with SARS-CoV-2 Infection independently of viral RNA. Using virus-like particle (VLP) systems and in vitro Infection models, we demonstrate that NP is secreted in a vesicle-free form via type I unconventional protein secretion (UPS) pathway. This process is regulated by NP phosphorylation and oligomerization, coordinated by viral structural proteins, and dependent on membrane components including heparan sulfate proteoglycans (HSPGs) and phosphatidylinositol 4,5-bisphosphate (PI (4,5) P2). Secreted NP is preferentially taken up by granulocytes and induces the release of inflammatory cytokines, including IL-6 and TNF-α. Our findings shed a light on the secretion mechanism of this pro-inflammatory NP, highlighting it as a potential therapeutic target for COVID-related systemic inflammation.

Keywords
COVID-19; CP: microbiology; SARS-CoV-2; inflammatory cytokines; nucleocapsid protein; oligomerization; phosphorylation; unconventional protein secretion.
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