2. Academic Validation
  3. Nuclear membrane protein SUN2 promotes replication of flaviviruses through modulating cytoskeleton reorganization mediated by NS1

Nuclear membrane protein SUN2 promotes replication of flaviviruses through modulating cytoskeleton reorganization mediated by NS1

  • Nat Commun. 2024 Jan 5;15(1):296. doi: 10.1038/s41467-023-44580-6.
Yanxia Huang # 1 2 3,  Qinyu Peng # 1 2,  Xu Tian # 1 2,  Cancan Chen 4,  Xuanfeng Zhu 1 2,  Changbai Huang 1 2,  Zhiting Huo 1 2,  Yang Liu 5,  Chao Yang 6 7,  Chao Liu 8 9,  Ping Zhang 10 11
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.
  • 2 Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
  • 4 Department of Pathology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
  • 5 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 6 Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. ychao@mail.sysu.edu.cn.
  • 7 Department of Neurosurgery, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Guangxi, China. ychao@mail.sysu.edu.cn.
  • 8 Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China. liuchao9@mail.sysu.edu.cn.
  • 9 Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. liuchao9@mail.sysu.edu.cn.
  • 10 Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China. zhangp36@mail.sysu.edu.cn.
  • 11 Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. zhangp36@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 38177122 DOI: 10.1038/s41467-023-44580-6
Abstract

Cytoskeleton is extensively recruited by flaviviruses for their Infection. In this study, we uncovered an essential role of a nuclear membrane protein, SAD1/UNC84 domain protein 2 (SUN2) linking Cytoskeleton and nucleoskeleton in the Flavivirus replication. CRISPR/Cas9-mediated knockout of SUN2, but not SUN1, significantly reduces the replication of Zika virus (ZIKV), Dengue virus (DENV), and Japanese encephalitis virus (JEV). In contrast, SUN2 does not affect the Infection of non-flaviviridae RNA viruses. All three regions of SUN2 are required for its proviral effect. Mechanistically, SUN2 facilitates rearrangement of Cytoskeleton and formation of replication organelles induced by viral Infection, and hence promotes viral RNA synthesis. SUN2 is required for the interaction between Cytoskeleton actin and ZIKV nonstructural protein 1 (NS1). Expression of dominant negative Nesprin-1 and Nesprin-2, which connect SUN2 to Cytoskeleton proteins, alleviates the interaction between actin and NS1 and reduces viral replication levels. In a neonatal mouse Infection model, SUN2 knockout dramatically alleviates the in vivo ZIKV replication and development of neuropathology. This work elucidates that recruitment of Cytoskeleton proteins by Flavivirus is coordinated by nuclear membrane proteins SUN2 and Nesprins, providing evidence for a link between nuclear membrane proteins and Flavivirus infection.

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