Vitamin D receptor deletion leads to reduced level of IkappaBalpha protein through protein translation, protein-protein interaction, and post-translational modification

Int J Biochem Cell Biol. 2010 Feb;42(2):329-36. doi: 10.1016/j.biocel.2009.11.012. Epub 2009 Nov 30.


Vitamin D receptor plays an essential role in the regulation of inflammation. Previous studies demonstrate that vitamin D receptor negatively modulates the proinflammatory NF-kappaB pathway. However, it is unknown how vitamin D receptor regulates IkappaBalpha, the endogenous inhibitor of NF-kappaB. Here we investigated the molecular mechanism of vitamin D receptor deletion and IkappaBalpha expression. We found that cells lacking vitamin D receptor had significantly increased levels of IkappaBalpha mRNA and simultaneously decreased levels of IkappaBalpha protein. Lacking vitamin D receptor abolished its binding to the IkappaBalpha promoter. Moreover, the levels of protein translation regulators and the rate of protein synthesis were both decreased in cells lacking vitamin D receptor. At the post-translational level, IkappaBalpha ubiquitination was enhanced, indicating increased degradation of IkappaBalpha in the absence of vitamin D receptor. We further transfected cells with a plasmid carrying either wild-type or mutant IkappaBalpha. The expression of wild-type IkappaBalpha was much higher in the cells with vitamin D receptor than in the cells without vitamin D receptor, whereas the expression of exogenous IkappaBalpha was equally high in both cell lines. In summary, vitamin D receptor deletion affects IkappaBalpha through mRNA transcription, protein translation, protein-protein interaction, post-translational modification, and protein degradation, thus reducing the level of IkappaBalpha protein. Cells lacking vitamin D receptor are known in a proinflammatory state with activation of NF-kappaB. Our study provides new insight into vitamin D receptor regulation of an inhibitor of NF-kappaB in inflammation. Deletion of vitamin D receptor contributes to the activation of NF-kappaB on multiple levels.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Alleles
  • Animals
  • Cell Line
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gene Deletion
  • Gene Expression Regulation
  • I-kappa B Proteins / biosynthesis*
  • I-kappa B Proteins / metabolism*
  • Inflammation / metabolism
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Processing, Post-Translational*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Calcitriol / deficiency*
  • Receptors, Calcitriol / genetics*
  • Receptors, Calcitriol / metabolism
  • Transcription, Genetic
  • Ubiquitination
  • eIF-2 Kinase / metabolism


  • Eukaryotic Initiation Factor-2
  • I-kappa B Proteins
  • NF-kappa B
  • Nfkbia protein, mouse
  • RNA, Messenger
  • Receptors, Calcitriol
  • NF-KappaB Inhibitor alpha
  • eIF-2 Kinase
  • Proteasome Endopeptidase Complex