Tumor necrosis factor alpha and inflammation disrupt the polarity complex in intestinal epithelial cells by a posttranslational mechanism

Anastasia Mashukova, Flavia A. Wald, Pedro J Salas

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Inflammatory processes disrupt the barrier function in epithelia. Increased permeability often leads to chronic of inflammation. Important among other cytokines, tumor necrosis factor alpha (TNF-α) initiates an NF-κB-mediated response that leads to upregulation of myosin light chain kinase (MLCK), a hallmark of the pathogenesis of inflammatory bowel disease. Here, we found that two components of the evolutionarily conserved organizer of tight junctions and polarity, the polarity complex (atypical protein kinase C [aPKC]-PAR6-PAR3) were downregulated by TNF-α signaling in intestinal epithelial cells and also in vivo during intestinal inflammation. Decreases in aPKC levels were due to decreased chaperoning activity of Hsp70 proteins, with failure of the aPKC rescue machinery, and these effects were rescued by NF-κB inhibition. Comparable downregulation of aPKC shRNA phenocopied effects of TNF-α signaling, including apical nonmuscle myosin II accumulation and myosin light chain phosphorylation. These effects, including ZO-1 downregulation, were rescued by overexpression of constitutively active aPKC. We conclude that this novel mechanism is a complementary effector pathway for TNF-α signaling.

Original languageEnglish
Pages (from-to)756-765
Number of pages10
JournalMolecular and Cellular Biology
Volume31
Issue number4
DOIs
StatePublished - Feb 1 2011

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Tumor Necrosis Factor-alpha
Epithelial Cells
Inflammation
Down-Regulation
Myosin Type II
Myosin-Light-Chain Kinase
Myosin Light Chains
Tight Junctions
Inflammatory Bowel Diseases
Small Interfering RNA
Permeability
Up-Regulation
Epithelium
Phosphorylation
PKC-3 protein
Cytokines
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Tumor necrosis factor alpha and inflammation disrupt the polarity complex in intestinal epithelial cells by a posttranslational mechanism. / Mashukova, Anastasia; Wald, Flavia A.; Salas, Pedro J.

In: Molecular and Cellular Biology, Vol. 31, No. 4, 01.02.2011, p. 756-765.

Research output: Contribution to journalArticle

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