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Homotypic endoplasmic reticulum membrane tethering is critical for flavivirus replication
Biorxiv : the Preprint Server for Biology
|December 15, 2025
Summary
The endoplasmic reticulum protein atlastin-2 (ATL2) organizes viral replication organelles essential for flavivirus infection. Inhibiting ATL2
Area of Science:
- Virology
- Cell Biology
- Molecular Biology
Background:
- Flaviviruses infect millions globally, relying on host cell machinery for replication.
- Flavivirus replication occurs within endoplasmic reticulum (ER)-derived viral replication organelles (vROs).
- Mechanisms of vRO biogenesis and membrane rearrangement remain poorly understood.
Purpose of the Study:
- To investigate the role of cellular ER remodeling proteins in flavivirus vRO formation.
- To determine if atlastin-2 (ATL2) is involved in organizing vROs during flavivirus infection.
- To explore ATL2 as a potential therapeutic target for flavivirus infections.
Main Methods:
- Confocal and electron microscopy to visualize vROs and ATL2.
- ATL2 depletion and knockout cell models.
- Mutational analysis of ATL2.
- Inhibition of ATL2 activity using synthetic peptides.
- Quantification of viral replication and innate immune responses.
Main Results:
- ATL2 depletion reduced vRO spatial distribution and viral production.
- ATL2 was observed to accumulate at vRO formation sites.
- A fusion-defective ATL2 mutant rescued DENV and ZIKV replication.
- ATL2 inhibition significantly reduced DENV replication in various cell types.
Conclusions:
- Atlastin-2 (ATL2) plays a conserved role in organizing vROs for flavivirus replication.
- Membrane tethering by ATL2 is critical for vRO biogenesis and limiting immune activation.
- Targeting ATL2-mediated membrane organization offers a potential strategy to inhibit flavivirus replication.
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