The Hippo pathway is conserved across eukaryotes and controls key biological processes, including cell growth and organ development. Notably, humans with biallelic loss-of-function mutations in the Hippo kinase gene MST1 suffer from combined immunodeficiency, including recurrent infections of herpes simplex virus (HSV), implicating the pathway in host immune regulation. We investigated the role of MST1 and its homolog MST2 in HSV-1 infection. We found that human epithelial cells HEp-2 proteolytically converted full-length MST1/2 into smaller N-terminal fragments (MST1/2-NT) to enhance cell apoptosis in response to the HSV-1 infection. Moreover, while infection by mutants lacking ICP0 or US3 elevated the production of MST1/2-NT and apoptosis, the overexpression of MST1-NT significantly reduced HSV-1 replication, revealing anti-viral properties of MST1/2 cleavage and the viral counteractions by ICP0 and US3. Consistently, we discovered that MST1/2-NT production, which was high in {Delta}ICP0-infected HEp-2 cells, was completely diminished in cells permissive to the {Delta}ICP0 infection, linking the counteraction against host MST1/2 cleavage to ICP0 functions. In addition, host caspases cleaved MST1/2 with differential preferences toward MST1 or MST2 in different infection contexts, indicating multiple regulations on the MST1/2-NT production during HSV-1 infection. While double-knockouts of MST1/2 in HEp-2 cells had marginal effects on wild type HSV-1 replication, it substantially reduced the early intake of {Delta}ICP0 DNA, suggesting a role of full-length MST1/2 in early infection. Altogether, these results uncover the novel and distinct roles of full-length and cleaved Hippo kinases during HSV-1 infection and their multifaceted interactions with ICP0.
St. Louis, B. M., Guha, U., Lee, P.-C., Gu, H.
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