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Access Type
WSU Access
Date of Award
January 2023
Degree Type
Thesis
Degree Name
M.S.
Department
Biological Sciences
First Advisor
Pei-Chung Lee
Abstract
The mammalian STE20-like-kinases, MST1 and MST2, are the initiator kinases in the highly conserved Hippo pathway. The Hippo pathway regulates cell proliferation and differentiation through modulating activity of the transcriptional regulators, large tumor Yes-associated protein 1 (YAP1) and the transcriptional co-activator with PDZ-binding motif (TAZ). Furthermore, disruption of MST1/2 are shown to induce tumorigenesis and lead to cancers. This thesis outlines the novel discovery in which we have found a unique proteolytic modification generating an N-terminal fragment of these kinases upon challenging with virulent Legionella pneumophila. We have found this cleavage event can occur in response to a series of pathogen- and damage-associated molecular patterns including ATP and nigericin. Interestingly, cleavage of MST1/2 did not require the NLRP3 inflammasome, but requires the presence of the NLRC4 inflammasome, introducing a novel link between the Hippo kinases and specific inflammasome activation. Using Mst1/2 double knockout macrophages generated by CRISPR/Cas9, we demonstrate a unique role for MST1/2 in triggering apoptotic programmed cell death and this cleavage event and respective N-terminal fragment are highly associated with known apoptotic signatures including poly-ADP-ribose polymerase-1 cleavage, caspase-3 activation, and histone H2AX phosphorylation. Uniquely, this cleavage event is specific to the invading pathogen and host activated inflammasome pathway, indicating a novel role for these kinases in host immunity and limiting bacterial pathogenesis.
Recommended Citation
Quagliato, Sydney Marie, "Inflammatory Molecular Patterns Trigger Processing Of The Hippo Kinases, Mst1 And Mst2, To Activate Cell Death In Macrophages" (2023). Wayne State University Theses. 926.
https://digitalcommons.wayne.edu/oa_theses/926