A Host Regulatory Circuit of HSV Gene Expression

HSV-1 is a persistent pathogen within society due to its ability to establish a lifelong infection within the host, causing severe symptoms in a cohort of those infected. HSV-1 alternates intermittently between productive and latent cycles, where the immediate-early protein ICP0 plays a critical role in driving lytic replication and reactivation from latency. During this complex process, HSV-1 triggers STING, a host factor that inhibits viral infection. It is well established that STING mediates antiviral immunity by inducing type I IFN. Additionally, STING activates autophagy to regulate HSV-1 replication. While poorly understood, STING is also reported to limit HSV-1 replication independently of IFN. However, exactly how STING inhibits HSV-1 remains unresolved. This thesis intends to address this fundamental question. This research revealed that STING downregulates the expression of ICP0, leading to the inhibition of viral production. Through genetic analysis, it was observed that STING facilitates proteasomal degradation of ICP0 via K11- and K48-linked ubiquitination. Furthermore, TBK1 mirrors the results of STING, independently of IFN, upon viral infection. As such, ablation of STING or TBK1 rescues viral production. Mechanistically, STING acts with TBK1 and the E3 ligase TRIM23. This model supports the idea that STING serves as a scaffold protein, recruiting TBK1 and TRIM23. This complex targets ICP0 for polyubiquitination and subsequent proteasomal degradation. Therefore, in addition to inducing IFN and promoting autophagy, STING directly regulates HSV immediate-early gene expression. These data indicate that a previously unrecognized regulatory circuit exists, which may control not only lytic but also latent HSV infection.

Author dc:creator

• Eric Krawczyk (15124854)

• Host-Viral Interaction
• HSV

Statement dc:rights

• In Copyright
• Open Access after 2028-01-01

DOI dc:identifier

https://doi.org/10.25417/uic.31451935.v1

OAI identifier oai:identifier

oai:figshare.com:article/31451935