Mechanism of IFN-γ-induced endocytosis of tight junction proteins: Myosin II-dependent vacuolarization of the apical plasma membrane

Markus Utech, Andrei I. Ivanov, Stanislav N. Samarin, Matthias Bruewer, Jerrold R. Turner, Randall J. Mrsny, Charles A. Parkos, Asma Nusrat

Research output: Contribution to journalArticlepeer-review

302 Citations (SciVal)

Abstract

Disruption of epithelial barrier by proinflammatory cytokines such as IFN-ã represents a major pathophysiological consequence of intestinal inflammation. We have previously shown that IFN-γ increases paracellular permeability in model T84 epithelial cells by inducing endocytosis of tight junction (TJ) proteins occludin, JAM-A, and claudin-1. The present study was designed to dissect mechanisms of IFN-γ-induced endocytosis of epithelial TJ proteins. IFN-γ treatment of T84 cells resulted in internalization of TJ proteins into large actin-coated vacuoles that originated from the apical plasma membrane and resembled the vacuolar apical compartment (VAC) previously observed in epithelial cells that lose cell polarity. The IFN-γ dependent formation of VACs required ATPase activity of a myosin II motor but was not dependent on rapid turnover of F-actin. In addition, activated myosin II was observed to colocalize with VACs after IFN-γ exposure. Pharmacological analyses revealed that formation of VACs and endocytosis of TJ proteins was mediated by Rho-associated kinase (ROCK) but not myosin light chain kinase (MLCK). Furthermore, IFN-γ treatment resulted in activation of Rho GTPase and induced expressional up-regulation of ROCK. These results, for the first time, suggest that IFN-γ induces endocytosis of epithelial TJ proteins via RhoA/ROCK-mediated, myosin II-dependent formation of VACs.

Original languageEnglish
Pages (from-to)5040-5052
Number of pages13
JournalMolecular Biology of the Cell
Volume16
Issue number10
DOIs
Publication statusPublished - 29 Jul 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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