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MG132-mediated inhibition of rabies virus replication via the Nrf2/SQSTM1/PINK1/Parkin autophagy pathway
Ying Lin Chi1, Nuo Yang1, Yuan Xie1,2
1Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, NHC Key Laboratory of Biosafety, Chinese Center for Disease Control and Prevention, No. 155 Changbai Road, Beijing, 102206, Changping, P. R. China.
Abstract:
Rabies virus (RABV), a fatal neurotropic virus, still lacks effective antiviral drugs for treatment once symptoms appear. MG132 acts as a novel therapeutic agent against viral infection, inhibits the degradation of nuclear factor erythroid-derived 2-like 2 (Nfe2l2; Nrf2), and enhances SQSTM1 expression in mouse hypothalamic organotypic cultures. Rapamycin-induced autophagy and Parkin-mediated mitophagy could also be inhibited by MG132. Autophagy signaling was triggered by RABV replication, but the antiviral effects of MG132 against RABV remained unclear. Here, we showed that MG132 exerted potent inhibitory activity against different viral strains (CVS-11 and CTN strains), with an efficacy comparable to that of ribavirin and higher than that of T705 in vitro. We further demonstrated that MG132 inhibited RABV replication by disrupting the Nrf2/SQSTM1/PINK1/Parkin pathway, with SQSTM1 acting as a key mediator. MG132 also prevented SQSTM1 degradation and enhanced colocalization between SQSTM1 and PINK1/Parkin. In vivo, MG132 (10 mg/kg) attenuated body weight loss and prolonged survival of RABV-infected mice by 40%. Overall, our findings indicated that MG132 inhibits RABV replication via the Nrf2/SQSTM1/PINK1/Parkin-related autophagy pathway and merits further investigation as an potential anti-RABV drug.
Insights
MG132 shows promise as an antiviral drug against rabies virus (RABV). It inhibits RABV replication by targeting the Nrf2/SQSTM1/PINK1/Parkin pathway, prolonging survival in infected mice.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Rabies virus (RABV) infection is fatal and lacks effective treatments after symptom onset.
- MG132 is a proteasome inhibitor with potential antiviral properties, affecting pathways like Nrf2 and autophagy.
- The precise antiviral mechanism of MG132 against RABV was not fully understood.
Purpose of the Study:
- To investigate the antiviral activity and mechanism of MG132 against RABV.
- To evaluate MG132 as a potential therapeutic agent for rabies.
Main Methods:
- In vitro antiviral assays comparing MG132 with ribavirin and T705 against different RABV strains.
- Analysis of the Nrf2/SQSTM1/PINK1/Parkin pathway and autophagy markers in MG132-treated cells.
- In vivo studies in mice to assess MG132's efficacy in reducing disease severity and prolonging survival.
Main Results:
- MG132 demonstrated potent in vitro inhibition of RABV replication, comparable to ribavirin and superior to T705.
- MG132 disrupted the Nrf2/SQSTM1/PINK1/Parkin pathway, preventing SQSTM1 degradation and enhancing its colocalization with PINK1/Parkin.
- In vivo, MG132 treatment significantly attenuated weight loss and extended survival by 40% in RABV-infected mice.
Conclusions:
- MG132 effectively inhibits RABV replication through modulation of the Nrf2/SQSTM1/PINK1/Parkin-related autophagy pathway.
- MG132 shows significant therapeutic potential as an anti-rabies drug and warrants further investigation.
