Date Thesis Awarded
Honors Thesis -- Access Restricted On-Campus Only
Bachelors of Science (BS)
Shantá D. Hinton
Lizabeth A. Allison
Cells carry out their day to day functions through the cellular work horses, proteins. Proteins work together like bees in a hive, each having its own specific task to accomplish. This specificity creates a fine-tuned division of labor where different types of proteins work together, completing their own work for the overall functioning of the cell. This division of labor can be mapped out nicely with cellular pathways. One such pathway is the stress response pathway. One of the major “workers” in this pathway is MK-STYX [MAPK (mitogen-activated protein kinase) phosphoserine/threonine/tyrosine-binding protein]. MK-STYX is a pseudophosphatase, a member of the dual-specificity family subfamily of MAPK phosphatases (MKPs) that lack the essential nucleophilic cysteine in its signature motif required for catalytic activity. MK-STYX maintains its three-dimensional fold and ability to bind proteins; it is involved in cellular pathways such as stress response, apoptosis, and neuronal differentiation. Previously, we reported that MK-STYX interacts with G3BP-1 [Ras-GAP (GTPAse-activating protein) SH3 (Src homology 3) domain binding protein-1], and inhibits stress granule formation. Stress granules, cytoplasmic storage sites for mRNA, form as a protective mechanism against stress caused by UV irradiation, hypoxia, and heat shock. Stress induces stress granules, and involves many cellular mechanisms such as post-translational modifications, protein-protein interactions, and microtubule networks. Furthermore, stress granules are targeted and cleared by autophagy, an initiated response to cellular stress. It is responsible for the degradation of cellular components. Therefore, autophagy is essential for cellular degradation. Since autophagy and MK-STYX each negatively affects stress granule assembly, we sought to determine whether MK-STYX has a role in autophagy. Pursuing the role of MK-STYX in regulating autophagy in this thesis research will enhance our understanding of MK-STYX’s mechanism in the stress response pathway. Our studies show that MK-STYX causes cytosolic TFEB (Transcription factor E-Box; the autophagy “master switch”) to localize to the perinuclear space independent of nutrient status. Whereas, MK-STYXactive (active mutant in which catalytic activity has been “restored”), did not show this phenotype, suggesting that the catalytic signature motif of MK-STYX may play a role in stress response. TFEB is also found to localize to the lysosomal surface, acting as negative regulator of lysosomal and autophagosomal biogenesis. MK-STYX alters lysosomal and autophagosomal dynamics; oversized lysosomes are observed in the presence of MK-STYX. Furthermore, autophagosomes localize to the distal ends of HEK/293 cellular extensions in the presence of MK-STYX. Autophagy plays a major role in major cellular processes ranging from initial developmental stages to the onset of progressive human pathologies such as neurodegenerative diseases and cancer. This thesis research suggests that MK-STYX may have an important role in autophagy, illuminating the importance of pseudoenzymes in regulating critical cellular pathways.
Christian, Patrick, "Beyond "self-eating": The Role of the Pseudophosphatase MK-STYX in Regulating Autophagy" (2017). Undergraduate Honors Theses. William & Mary. Paper 1078.
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