Prohibitin Inhibits Tumor Necrosis Factor alpha–induced Nuclear Factor-kappa B Nuclear Translocation via the Novel Mechanism of Decreasing Importin α3 Expression

作者：Arianne L. Theiss, Aaron K. Jenkins, Ngozi I. Okoro, Jan‐Michael Axel Klapproth, Didier Merlin, Shanthi V. Sitaraman · 发表于：Molecular Biology of the Cell · 年份：2009 · DOI：10.1091/mbc.e09-05-0361 · 被引用次数：70 · 研究领域：Nuclear Structure and Function、Trace Elements in Health、RNA Research and Splicing

Expression of prohibitin 1 (PHB), a multifunctional protein in the cell, is decreased during inflammatory bowel disease (IBD). Little is known regarding the regulation and role of PHB during intestinal inflammation. We examined the effect of tumor necrosis factor alpha (TNF-alpha), a cytokine that plays a central role in the pathogenesis of IBD, on PHB expression and the effect of sustained PHB expression on TNF-alpha activation of nuclear factor-kappa B (NF-kappaB) and epithelial barrier dysfunction, two hallmarks of intestinal inflammation. We show that TNF-alpha decreased PHB protein and mRNA abundance in intestinal epithelial cells in vitro and in colon mucosa in vivo. Sustained expression of prohibitin in intestinal epithelial cells in vitro and in vivo (prohibitin transgenic mice, PHB TG) resulted in a marked decrease in TNF-alpha-induced nuclear translocation of the NF-kappaB protein p65, NF-kappaB/DNA binding, and NF-kappaB-mediated transcriptional activation despite robust IkappaB-alpha phosphorylation and degradation and increased cytosolic p65. Cells overexpressing PHB were protected from TNF-alpha-induced increased epithelial permeability. Expression of importin alpha3, a protein involved in p50/p65 nuclear import, was decreased in cells overexpressing PHB and in colon mucosa of PHB TG mice. Restoration of importin alpha3 levels sustained NF-kappaB activation by TNF-alpha during PHB transfection. These results suggest that PHB inhibits NF-kappaB nuclear translocat...