The Role of Selenoprotein K in DHHC6-Mediated Protein Palmitoylation and the Impact on Immune Cell Function

Fredericks, Gregory
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[Honolulu] : [University of Hawaii at Manoa], [May 2016]
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This dissertation is a summary of my research which has had one central goal: to discover the function of selenoprotein K (SelK) at the cellular level. Due to the high expression of SelK in immune cells, and the focus of immunological studies in the Hoffmann laboratory, I have specifically focused on understanding the role of SelK in immune cells. SelK, a single-pass endoplasmic reticulum (ER) membrane protein, was initially found by the Hoffmann laboratory to be important in immune cell calcium (Ca2 +) flux and activation, however the mechanism was not understood. In a subsequent study we found that SelK deficiency led to reduced palmitoylation of the receptor for oxidized LDL, CD36. Further studies found that SelK was important for the palmitoylation of yet another protein important for immune cell function, ASAP2. SelK deficiency leads to reduced levels of ASAP2 palmitoylation, thereby preventing its cleavage by the protease calpain, ultimately impairing Fc receptor (FcR)-mediated macrophage phagocytosis. The importance of SelK in the palmitoylation of multiple proteins led us to examine whether SelK was involved in the palmitoylation of ER-resident protein(s) that are required for proper Ca2 + flux. Chapter 2 details this work, which shows how SelK enhances the ability of the protein acyltransferase (PAT) DHHC6 to palmitoylate the inositol-1,4,5-triphosphate receptor (IP3R). Palmitoylation of the IP3R is required for the stability and function of this Ca2 + channel protein and thereby explains the importance of SelK in Ca2 + flux. In Chapter 3 I discuss the possible mechanisms by which SelK is modulating DHHC6 to enhance the protein palmitoylation reaction and present the ongoing studies being conducted to examine these theories. This chapter concludes with a discussion of the implications of these studies and identifies the future studies that will be necessary to fully understand the role of SelK in DHHC6-mediated protein palmitoylation.
Ph.D. University of Hawaii at Manoa 2016.
Includes bibliographical references.
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Theses for the degree of Doctor of Philosophy (University of Hawaii at Manoa). Cell and Molecular Biology
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