MARCH8 inhibits pseudorabies virus replication by trapping the viral cell-to-cell fusion complex in the trans-Golgi
Cui-Hong Rao1, Rui Huang1, Yuan-Zhe Bai1
1State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001, China.
Abstract:
The membrane-associated RING-CH 8 protein (MARCH8), a member of the E3 ubiquitin ligase family, has broad-spectrum antiviral activity. However, some viruses hijack MARCH8 to promote virus replication, highlighting its dual role in the viral lifecycle. Most studies on MARCH8 have focused on RNA viruses, leaving its role in DNA viruses largely unexplored. Pseudorabies virus (PRV) is a large DNA virus that poses a potential threat to humans. In this study, we found that MARCH8 inhibited PRV replication at the cell-to-cell fusion stage. Interestingly, our findings proved that MARCH8 blocks gB cleavage by recruiting furin but this activity does not inhibit viral infection in vitro. Furthermore, we confirmed that MARCH8 inhibits cell-to-cell fusion independent of its E3 ubiquitin ligase activity but dependent on the interaction with the cell-to-cell fusion complex (gB, gD, gH, and gL). Finally, we discovered that the distribution of the cell-to-cell fusion complex is significantly altered and trapped within the trans-Golgi network. Overall, our results indicate that human MARCH8 acts as a potent antiviral host factor against PRV via trapping the cell-to-cell fusion complex in the trans-Golgi network.
Insights
The membrane-associated RING-CH 8 protein (MARCH8) inhibits Pseudorabies virus (PRV) DNA virus replication by trapping its fusion complex in the trans-Golgi network, acting as a host antiviral factor.
Area of Science:
- Virology
- Cell Biology
- Molecular Biology
Background:
- The membrane-associated RING-CH 8 protein (MARCH8) is an E3 ubiquitin ligase with known antiviral properties.
- MARCH8's role in DNA virus replication is understudied, despite its involvement in RNA virus lifecycles.
- Pseudorabies virus (PRV) is a significant DNA virus with potential human health implications.
Purpose of the Study:
- To investigate the role of human MARCH8 in the replication of the DNA virus, Pseudorabies virus (PRV).
- To elucidate the mechanism by which MARCH8 affects PRV infection and replication.
Main Methods:
- Investigated MARCH8's effect on PRV replication at the cell-to-cell fusion stage.
- Analyzed MARCH8's interaction with viral proteins (gB, gD, gH, gL) and cellular machinery (furin, trans-Golgi network).
- Assessed the dependence of MARCH8's antiviral activity on its E3 ubiquitin ligase function.
Main Results:
- MARCH8 significantly inhibits PRV replication by interfering with cell-to-cell fusion.
- MARCH8 recruits furin to block gB cleavage, but this does not inhibit viral infection in vitro.
- MARCH8 inhibits cell-to-cell fusion independently of its E3 ligase activity, through interaction with the viral fusion complex (gB, gD, gH, gL).
- MARCH8 traps the cell-to-cell fusion complex within the trans-Golgi network, altering its distribution.
Conclusions:
- Human MARCH8 functions as a potent antiviral host factor against PRV.
- MARCH8 inhibits PRV by sequestering the viral cell-to-cell fusion complex in the trans-Golgi network.
- This mechanism highlights a novel antiviral strategy involving host protein interaction with viral fusion machinery.
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