Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 176, Issue 1, Pages 134-145Publisher
AMER SOC INVESTIGATIVE PATHOLOGY, INC
DOI: 10.2353/ajpath.2010.090220
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Funding
- National Institutes of Health [DK 55679, DK 61379, DK 72564]
- Emory epithelial pathobiology research development [R24DK 064399]
- Medical Scientists Training Program [T32 GM008169-21]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK072564, R29DK055679, R01DK061379, R24DK064399, R01DK055679, R01DK059888] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008169, R01GM054712] Funding Source: NIH RePORTER
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Formation of the epithelial barrier and apico-basal cell polarity represent two characteristics and mutually dependent features of differentiated epithelial monolayers. They are controlled by special adhesive structures, tight junctions (TJs), and polarity protein complexes that define the apical and the basolateral plasma membrane. The functional interplay between TJs and polarity complexes remains poorly understood. We investigated the role of Scribble, a basolateral polarity protein and known tumor suppressor, in regulating TJs in human intestinal epithelium. Scribble was enriched at TJs in T84 and SK-CO15 intestinal epithelial cell monolayers and sections of normal human colonic mucosa. siRNA-mediated knockdown of Scribble in SK-CO15 cells attenuated development of epithelial barrier and inhibited TJ reassembly independently of other basolateral polarity proteins Lgl-1 and Dlg-1. Scribble selectively coimunoprecipitated with TJ protein ZO-1, and ZO-1 was important for Scribble recruitment to intercellular junctions and TJ reassembly. Lastly, Scribble was mislocalized from TJs and its expression down-regulated in interferon-gamma-treated T84 cell monolayers and inflamed human intestinal mucosa in vivo. We conclude that Scribble is an important regulator of TJ functions and plasticity in the intestinal epithelium. Down-regulation of Scribble may mediate mucosal barrier breakdown during intestinal inflammation. (Am J Pathol 2010, 176:134-145; DOI: 10.2353/ajpath.2010.090220)
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