Selenium (Se) is an essential micronutrient important for many aspects of human health, including optimal immune responses. The biological effects of Se are exerted mainly through its incorporation into selenoproteins as the amino acid, selenocysteine (Sec). Twenty-five selenoproteins have been identified in humans, all but one of which also exist as Sec-containing proteins in mice and rats. One selenoprotein that we have shown to be important for optimal immune responses is the endoplasmic reticulum (ER) transmembrane selenoprotein K (Selk). Selk expression is expressed highest in immune cells and is sensitive to levels of Se intake. The main goal of our first funding period was to understand how Selk regulates immune cell function and to use our novel Selk-/- mouse model to determine the role of Selk for in vivo immunity. We were successful in uncovering a role for Selk in generating the calcium (Ca2+) flux that occurs during receptor-mediated activation in immune cells including T and B cells, neutrophils, and macrophages. Our new data have revealed that Selk deficiency leads to impaired Ca2+ flux due to a defect in palmitoylation of the Ca2+ channel protein, inositol-1,4,5-triphosphate receptor (IP3R), in the ER membrane of immune cells. IP3R-driven Ca2+ flux plays a central role in immune cell activation and Selk deficiency was shown in our studies to influence a wide variety of immune responses including anti-viral immunity, peritonitis, and atheroschlerosis. These findings have led to our central hypothesis that Selk functions as a cofactor for the palmitoyl acyl transferase, DHHC6, thereby promoting the palmitoyation of IP3R and other cellular proteins and this serves as a mechanism by which levels of dietary Se regulate immunity. Our innovative studies will definitively determine the role of Selk in the palmitoylation of the IP3R and other proteins and how this affects immune cell function. We also will take an important step toward translating our findings to human health by investigating how dietary Se and genetic polymorphisms are related to Selk expression and immune cell function in humans. We will accomplishment of the following specific aims:
Specific Aim 1. Determine the mechanisms by which Selk regulates palmitoylation of the IP3R.
Specific Aim 2. Identify cellular proteins that require Selk for palmitoylation and determine how palmitoylation regulates their function.
Specific Aim 3. To determine how Selk expression is regulated in human T cells and how this affects IP3R expression and T cell function.

Public Health Relevance

We have uncovered an important role for selenoprotein K in exerting the effects of dietary selenium on immune responses. The goal of this project is to determine the precise role this protein plays in regulating immune cell functions and contributing to optimal immunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mallia, Conrad M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Hawaii
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Marciel, Michael P; Khadka, Vedbar S; Deng, Youpeng et al. (2018) Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis. Oncotarget 9:13407-13422
Pitts, Matthew W; Hoffmann, Peter R (2018) Endoplasmic reticulum-resident selenoproteins as regulators of calcium signaling and homeostasis. Cell Calcium 70:76-86
Avery, Joseph C; Hoffmann, Peter R (2018) Selenium, Selenoproteins, and Immunity. Nutrients 10:
Marciel, Michael P; Rose, Aaron H; Martinez, Verena et al. (2018) Calpain-2 inhibitor treatment preferentially reduces tumor progression for human colon cancer cells expressing highest levels of this enzyme. Cancer Med 7:175-183
Norton, Robert L; Fredericks, Gregory J; Huang, Zhi et al. (2017) Selenoprotein K regulation of palmitoylation and calpain cleavage of ASAP2 is required for efficient Fc?R-mediated phagocytosis. J Leukoc Biol 101:439-448
Fredericks, Gregory J; Hoffmann, FuKun W; Hondal, Robert J et al. (2017) Selenoprotein K Increases Efficiency of DHHC6 Catalyzed Protein Palmitoylation by Stabilizing the Acyl-DHHC6 Intermediate. Antioxidants (Basel) 7:
Zhu, Chenghui; Zhang, Shuimei; Song, Chengwei et al. (2017) Selenium nanoparticles decorated with Ulva lactuca polysaccharide potentially attenuate colitis by inhibiting NF-?B mediated hyper inflammation. J Nanobiotechnology 15:20
Marciel, Michael P; Hoffmann, Peter R (2017) Selenoproteins and Metastasis. Adv Cancer Res 136:85-108
Cai, Zhihui; Dong, Liangbo; Song, Chengwei et al. (2017) Methylseleninic Acid Provided at Nutritional Selenium Levels Inhibits Angiogenesis by Down-regulating Integrin ?3 Signaling. Sci Rep 7:9445
Zhong, Wenbin; Yi, Qing; Xu, Bing et al. (2016) ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival. Nat Commun 7:12702

Showing the most recent 10 out of 29 publications