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mLST8 is essential for coronavirus replication and regulates its replication through the mTORC1 pathway
Yanan Fu1,2, Zhen Fu1,2, Zhelin Su1,2
1State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University , Wuhan, China.
Mbio
|June 28, 2023
Summary
Mammalian lethal with sec-13 protein 8 (mLST8) is a novel host factor critical for coronavirus (CoV) replication. Its depletion activates autophagy, inhibiting viral replication and offering a target for broad-spectrum antiviral drugs.
Area of Science:
- Virology
- Molecular Biology
- Cellular Biology
Background:
- Coronaviruses (CoVs) pose significant global health threats, necessitating understanding of host-viral interactions for replication.
- Identifying host factors exploited by CoVs is crucial for developing effective antiviral strategies.
- The role of mammalian lethal with sec-13 protein 8 (mLST8) in CoV replication was previously uncharacterized.
Purpose of the Study:
- To identify novel host factors essential for coronavirus replication.
- To elucidate the molecular mechanisms by which mLST8 influences CoV replication.
- To explore the therapeutic potential of targeting mLST8 or related pathways for broad-spectrum antiviral drug development.
Main Methods:
- Utilized inhibitor and knockout (KO) experiments to assess the role of mLST8 and mTORC1/mTORC2 in CoV replication.
- Investigated the impact of mLST8 KO on downstream signaling pathways, including ULK1 phosphorylation.
- Employed transmission electron microscopy to visualize the effects of mLST8 KO and autophagy activation on viral replication structures.
Main Results:
- mLST8 was identified as a critical host factor for CoV replication, with mTORC1 signaling being essential.
- mLST8 KO led to reduced ULK1 phosphorylation, promoting autophagy activation and antiviral replication.
- Both mLST8 KO and autophagy activation inhibited the formation of double-membrane vesicles and suppressed replication of multiple CoVs.
Conclusions:
- mLST8 is a novel host regulator of CoV replication, acting via the mTORC1-ULK1-autophagy axis.
- Autophagy activation downstream of mLST8 depletion impairs early viral replication, suggesting a conserved antiviral mechanism.
- Targeting mLST8 or modulating autophagy presents a promising strategy for developing broad-spectrum antiviral therapies against CoVs.
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