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Oxidative Folding of Interleukin-2 Is Impaired in Flavin-Deficient Jurkat Cells, Causing Intracellular Accumulation of Interleukin-2 and Increased Expression of Stress Response Genes¹

Gabriela Camporeale^* and Janos Zempleni^*,,2

Departments of ^* Nutritional Science and Dietetics, and Biochemistry, University of Nebraska at Lincoln, Lincoln, NE

²To whom correspondence should be addressed. E-mail: jzempleni2{at}unl.edu.

Secretory proteins such as interleukin (IL)-2 undergo oxidative folding (disulfide formation) in the endoplasmic reticulum (ER) before secretion. Studies in yeast have suggested that oxidative folding depends on the flavoprotein Ero1p; unfolded proteins accumulate in the ER, triggering cellular stress response. Here, human lymphoid cells (Jurkat cells) were used to model effects of cellular flavin supply on secretion of IL-2 (containing one disulfide bond) and cellular stress response. Cells were cultured in media containing 0.85, 3.1, 12.6 or 300.6 nmol/L riboflavin for 5 wk, representing severely deficient, moderately deficient, physiologic and pharmacologic plasma concentrations in humans, respectively. Transport rates of riboflavin were increased in severely and moderately deficient cells compared with cells cultured in physiologic medium; this increase was not sufficient to prevent intracellular depletion of riboflavin, as judged by glutathione reductase activity and intracellular concentrations of glutathione. Intracellular accumulation of IL-2 was greater in severely deficient cells than in other groups. Nevertheless, severely deficient cells secreted normal amounts of IL-2 into the extracellular space, mediated by increased transcriptional activity of the IL-2 gene. Riboflavin-deficient cells responded to intracellular accumulation of IL-2 with increased expression of genes encoding ubiquitin-activating enzyme E1 and X box-binding protein, consistent with cellular stress. These findings are consistent with the hypothesis that flavin deficiency may cause cellular stress by accumulation of unfolded proteins in human cells.

KEY WORDS: • endoplasmic reticulum • interleukin-2 • Jurkat cells • riboflavin • stress response

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