Role of Selenium in Age-Related Degeneration: Selenotranscriptome Hierarchy and Characterization of Selenoprotein H
Mosby, Terezie T.
Selenium (Se) is an essential trace element exerting its biological functions mainly through selenoproteins. Our lab has recently shown a paradoxical role of dietary Se at nutritional levels of intake in the delay of age-related degeneration while reducing longevity in mice carrying humanized telomeres. The first aim of this dissertation was to evaluate the effects of long-term dietary Se deficiency, aging, and sex on selenotranscriptome hierarchy in tissues. Four unique patterns in selenotranscriptomic changes were summarized. First, the responses of selenotranscriptomes to dietary Se deprivation and aging were sexually dimorphic. Second, a few selenoproteins responded to dietary Se deficiency and aging in parallel. Third, there were selenoproteins up-regulated by aging or dietary Se deprivation. Forth, some selenoproteins, especially those in testis, were upregulated by aging in mice on a Se-deficient diet. Selenoprotein H (SELH) is ranked low in selenoprotein hierarchy and its expression is tissue-specific and abundant during embryogenesis. SELH is a nucleolar DNA-binding protein with thioredoxin (Txn)-like fold and glutathione peroxidase activity. The known biological functions of SELH include redox regulation and suppression of cellular senescence and tumorigenesis. The second aim of this dissertation was to study the functional interactions of SELH with other selenoproteins and its protective effects against oxidative stress. A FLAG-tagged plasmid expressing wild-type SELH was constructed. Compared to standard cell culture conditions, additional sodium selenite (Na2SeO3) increased SELH expression at protein but not mRNA level when FLAG-SELH was overexpressed. In the absence of supplemental Na2SeO3, FLAG-SELH overexpression suppressed the expression of other selenoproteins such as glutathione peroxidase 1 (GPX1) and thioredoxin reductase 1 (TrxR1) at protein but not mRNA level. FLAG-SELH overexpression protected the cells against oxidative stress only when additional Na2SeO3 was added. Identification of FLAG-SELH-associated proteins confirmed its nucleolar location. Altogether, a distinctive set of selenoproteins is maintained under dietary Se deficiency in a tissue- and sex-specific manner during the aging process. While SELH is ranked low in selenoprotein hierarchy implying that it is dispensable, this nucleolar selenoprotein competes with other selenoproteins for Se and protects the cells against oxidative stress.