VZV gE Promotes STING Degradation via Midnolin-Proteasome Pathway to Inhibit cGAS-STING Signaling

Chen, L.; Dai, L.; Nie, S.; Zhao, Y.; Li, F.; Deng, X.; Liu, C.; Li, M.; Luo, Z.; Liu, Y.; Ge, W.; Liu, X.; Yi, Q.; Li, Y.; Pan, P.; Wang, X.

doi:10.1101/2025.01.13.632693

bioRxiv · 10.1101/2025.01.13.632693

VZV gE Promotes STING Degradation via Midnolin-Proteasome Pathway to Inhibit cGAS-STING Signaling

Chen, L.·Dai, L.·Nie, S.·Zhao, Y.·Li, F.·Deng, X.·Liu, C.·Li, M.·Luo, Z.·Liu, Y.·Ge, W.·Liu, X.·Yi, Q.·Li, Y.·Pan, P.·Wang, X.

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Abstract

Varicella-zoster virus (VZV) infects 85 million individuals annually and it is known for its intricate interplay with host cellular mechanisms, significantly impacting antiviral immune responses. Previous studies have highlighted the critical role of VZV glycoprotein E (gE) in virus-host interactions, but the precise mechanisms remain to be elucidated. Our results demonstrate that VZV gE interacts with STING, specifically through the gE (350-480aa) and STING (151-160aa) regions. This interaction predominantly involves incompletely glycosylated gE. Functional assays revealed that gE inhibits the cGAS-STING signaling pathway. gE enhances VZV proliferation and promotes STING degradation via the proteasome pathway, without affecting STING ubiquitination. We identified Midnolin as a mediator in this degradation process, with gE facilitating the interaction between STING and Midnolin. In vivo, gE expression in mice led to diminished antiviral responses upon HSV-1 infection, highlighting gEs role in modulating immune signaling. Our findings provide significant insights into VZVs evasion of host immune responses. By promoting STING degradation through an unconventional Midnolin-proteasome pathway, VZV gE effectively suppresses antiviral signaling, facilitating enhanced viral proliferation. The findings contribute significantly to the understanding of VZV pathogenesis and provide new therapeutic strategies against VZV.

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Chen, L., Dai, L., Nie, S., Zhao, Y., Li, F., Deng, X., Liu, C., Li, M., Luo, Z., Liu, Y., Ge, W., Liu, X., Yi, Q., Li, Y., Pan, P., Wang, X.. 2025-01-14. VZV gE Promotes STING Degradation via Midnolin-Proteasome Pathway to Inhibit cGAS-STING Signaling. https://doi.org/10.1101/2025.01.13.632693

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