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Coronavirus Nsp3 Hijacks CLTC to Modulate Autophagosome Nucleation for Promoting DMV Formation and Viral Replication
1State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, P. R. China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 21, 2026
Summary
Clathrin heavy chain (CLTC) is essential for coronavirus replication, forming double-membrane vesicles (DMVs) by interacting with viral protein nsp3. This discovery highlights CLTC and autophagosome nucleation as potential antiviral targets.
Area of Science:
- Virology
- Cell Biology
- Molecular Biology
Background:
- Double-membrane vesicles (DMVs) are critical for coronavirus replication but their formation is poorly understood.
- Existing tools limit dynamic analysis of DMV biogenesis during infection.
Purpose of the Study:
- To develop a live-cell imaging system for real-time visualization of DMV formation.
- To identify host factors involved in DMV biogenesis and coronavirus replication.
Main Methods:
- Developed a live-cell imaging system using a recombinant virus for real-time DMV visualization.
- Investigated the role of clathrin heavy chain (CLTC) in coronavirus replication.
- Analyzed the interaction between CLTC and viral nonstructural protein 3 (nsp3).
Main Results:
- Visualized DMV formation in real-time during authentic coronavirus infection.
- Identified clathrin heavy chain (CLTC) recruitment to DMV assembly sites.
- Demonstrated CLTC's essential role in diverse coronavirus replication but not in unrelated viruses.
- Uncovered a novel role for CLTC in viral replication organelle formation.
- Showed CLTC interacts with nsp3 and is required for autophagosome nucleation by maintaining the PI3K complex.
- Revealed that nsp3 hijacks CLTC-mediated membranes to form DMVs.
Conclusions:
- Clathrin heavy chain (CLTC) is a pivotal host factor essential for coronavirus replication.
- CLTC mediates DMV formation by facilitating autophagosome nucleation and subsequent hijacking by nsp3.
- CLTC and the autophagosome nucleation pathway represent promising targets for antiviral therapies.
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