2. Academic Validation
  3. Host specific sphingomyelin is critical for replication of diverse RNA viruses

Host specific sphingomyelin is critical for replication of diverse RNA viruses

  • Cell Chem Biol. 2024 Dec 19;31(12):2052-2068.e11. doi: 10.1016/j.chembiol.2024.10.009.
Shuo Han 1,  Xiaolei Ye 1,  Jintong Yang 2,  Xuefang Peng 1,  Xiaming Jiang 3,  Jin Li 4,  Xiaojie Zheng 1,  Xinchen Zhang 2,  Yumin Zhang 3,  Lingyu Zhang 1,  Wei Wang 2,  Jiaxin Li 1,  Wenwen Xin 1,  Xiaoai Zhang 1,  Gengfu Xiao 3,  Ke Peng 3,  Leike Zhang 3,  Xuguang Du 4,  Lu Zhou 5,  Wei Liu 6,  Hao Li 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China.
  • 2 School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
  • 4 State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
  • 5 School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: zhoulu@fudan.edu.cn.
  • 6 State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China. Electronic address: lwbime@163.com.
  • 7 State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China. Electronic address: lihao_1986@126.com.
PMID: 39566509 DOI: 10.1016/j.chembiol.2024.10.009
Abstract

Lipids and lipid metabolism play an important role in RNA virus replication, which typically occurs on host cell endomembrane structures in the cytoplasm through mechanisms that are not yet fully identified. We conducted genome-scale CRISPR screening and identified sphingomyelin synthase 1 (SMS1; encoded by SGMS1) as a critical host factor for Infection by severe fever with thrombocytopenia syndrome virus (SFTSV). SGMS1 knockout reduced sphingomyelin (SM) (d18:1/16:1) levels, inhibiting SFTSV replication. A helix-turn-helix motif in SFTSV RNA-dependent RNA polymerase (RdRp) directly binds to SM(d18:1/16:1) in Golgi apparatus, which was also observed in SARS-CoV-2 and lymphocytic choriomeningitis virus (LCMV), both showing inhibited replication in SGMS1-KO cells. SM metabolic disturbance is associated with disease severity of viral infections. We designed a novel SMS1 inhibitor that protects mice against lethal SFTSV Infection and reduce SARS-CoV-2 replication and pathogenesis. These findings highlight the critical role of SMS1 and SM(d18:1/16:1) in RNA virus replication, suggesting a broad-spectrum Antiviral strategy.

Keywords

Golgi apparatus; RNA viruses; antivirals; lipid metabolism; replication complex; sphingomyelin.

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