Biology subjects

St. Louis, B. M.

Publications and source records attributed to St. Louis, B. M..

3 recordsLinked to original sources

bioRxiv2026

Multifaceted regulations of HSV-1 ICP0 on the Anti-Viral Restrictions Imposed by the Host Hippo Kinases Reprogramming

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. ImportanceHSV poses serious threats to human health, ranging from cold sores to fatal brain infection. As a successful human pathogen, it deploys various viral proteins to counteract host defenses and subjugate host machinery, but mechanisms underlying these complex HSV-host interactions are not fully understood. For the first time, we report multifaceted interactions between the Hippo kinases and viral proteins during HSV-1 infection. We show that the Hippo kinases are converted to smaller fragments through protein cleavage in HSV-1 infected cells, and the cleaved Hippo fragments are accompanied by host cell death to execute their anti-viral activities. Moreover, multiple viral proteins contribute to counteracting this host defense, including ICP0, which executes a complex interplay with the Hippo kinases to promote infection. Understanding this new layer of virus-host interaction may pave the road to developing novel treatments for herpetic diseases.

microbiology↗

bioRxiv2025

Cleavage of the Hippo kinases and programmed cell death in murine macrophages exposed to sterile stimuli and bacterial pathogens

Mammalian STE20-like kinases MST1 and MST2 are the conserved Hippo kinases known for their importance in organ development and tumor suppression. Notably, humans and mice lacking these kinases have increased susceptibility to infection, indicating a role of MST1/2 in immunity. In macrophages that play a critical role in host immunity, MST1/2 are proteolytically cleaved to coordinate different forms of programmed cell death, including apoptosis and pyroptosis. This cleavage event occurs when the innate immune sensors, inflammasomes, are activated by the bacterial pathogen, Legionella pneumophila, or damage-associated molecular patterns. In this report, we determine MST1/2 cleavage in macrophages under various inflammatory conditions and challenges with pathogenic bacteria. The sterile molecules ATP and nigericin induce MST1/2 cleavage and apoptosis when the NLRP3 inflammasome and GSDMD-mediated pyroptosis are activated. Remarkably, in conditions without NLRP3 or GSDMD activation, MST1/2 are still cleaved by caspases to promote cell death in macrophages treated with these sterile molecules. During infection, wildtype macrophages trigger MST1/2 cleavage and apoptosis against L. pneumophila and Yersinia pseudotuberculosis but preferentially activate GSDMD-mediated pyroptosis against Pseudomonas aeruginosa and Salmonella enterica Typhimurium. Interestingly, GSDMD knockout macrophages opt to cleave MST1/2 and undergo apoptosis in response to P. aeruginosa and S. enterica, suggesting an interplay between GSDMD and MST1/2. Together, macrophages funnel apoptotic death signals through MST1/2 cleavage upon stimulation of the inflammatory molecules and pathogens, which illustrates the broad implications of the host Hippo kinases in infections and sterile inflammation.

microbiology↗

bioRxiv2023

The Hippo kinases control inflammatory Hippo signaling and restrict bacterial infection in eukaryotic phagocytes

The Hippo kinases MST1 and MST2 initiate a highly conserved signaling cascade called the Hippo pathway that limits organ size and tumor formation in animals. Intriguingly, pathogens hijack this host pathway during infection, but the role of MST1/2 in innate immune cells against pathogens is unclear. In this study, we generated Mst1/2 knockout macrophages to investigate the regulatory activities of the Hippo kinases in immunity. Transcriptomic analyses identified differentially expressed genes (DEGs) that are enriched in biological pathways, such as systemic lupus erythematosus, tuberculosis, and apoptosis. Surprisingly, pharmacological inhibition of the downstream components LATS1/2 in the canonical Hippo pathway did not affect expression of a set of immune DEGs, suggesting that MST1/2 control these genes via alternative inflammatory Hippo signaling. Moreover, MST1/2 may affect immune communication by influencing the release of cytokines, such as TNF, CXCL10, and IL-1ra. Comparative analyses of the single- and double-knockout macrophages revealed that MST1 and MST2 differentially regulate TNF release and expression of the immune transcription factor, MAF, demonstrating that the two homologous Hippo kinases individually play a unique role in innate immunity. Notably, MST1 and MST2 are both required for macrophages to activate apoptosis. Lastly, we demonstrated that the Hippo kinases are critical factors in mammalian macrophages and single-cell amoebae to restrict infection by Legionella pneumophila, Escherichia coli, and Pseudomonas aeruginosa. Together, these results uncover non-canonical inflammatory Hippo signaling in macrophages and the evolutionarily conserved role of the Hippo kinases in anti-microbial defense of eukaryotic hosts.

microbiology↗