Proteasome Inhibitor MG132 Facilitates Antiviral Effects by Inhibiting TFEB Degradation and Activating Autophagy

Abstract The ubiquitin-proteasome system, which serves as one of the most common cellular degradation pathways, plays a critical role in maintaining proteostasis. Yet, the correlation between the ubiquitin-proteasome system and antiviral defense remains to be defined. In this work, pharmacological inhibition of proteasomes via treatment with MG132, which inhibited proteasome activity during viral infection, facilitated antiviral effects in vitro. Similar to MG132, another proteasome inhibitor, bortezomib, effectively inhibited proteasome activity and exhibited antiviral effects. Guided by these findings, further assays demonstrated that MG132 blocked viral adsorption and internalization, which partially contributed to the antiviral effects. Meanwhile, MG132 inhibited TFEB degradation and promoted dephosphorylation of TFEB at Ser211, resulting in autophagy, which was associated with antiviral effects. Taken together, a key discovery of our study is the critical role of the proteasome inhibitor MG132 in promoting antiviral activity, providing valuable insights for the development of more effective antiviral strategies based on the autophagy signaling pathway mediated by TFEB.