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Vol. 18, Issue 11, 4565-4578, November 2007

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Desmoglein-2: A Novel Regulator of Apoptosis in the Intestinal Epithelium

Porfirio Nava^*,, Mike G. Laukoetter^*,,, Ann M. Hopkins, Oskar Laur^*, Kirsten Gerner-Smidt^*, Kathleen J. Green^||, Charles A. Parkos^*, and Asma Nusrat^*

*Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; Department of General Surgery, University of Muenster, D-48149 Muenster, Germany; UCD School of Medicine and Medical Science, University College, Dublin 4, Ireland; and ^||Northwestern University Feinberg School of Medicine, Chicago, IL 60611

Submitted May 9, 2007; Revised July 19, 2007; Accepted August 27, 2007
Monitoring Editor: M. Bishr Omary

Intestinal epithelial intercellular junctions regulate barrier properties, and they have been linked to epithelial differentiation and programmed cell death (apoptosis). However, mechanisms regulating these processes are poorly defined. Desmosomes are critical elements of intercellular junctions; they are punctate structures made up of transmembrane desmosomal cadherins termed desmoglein-2 (Dsg2) and desmocollin-2 (Dsc2) that affiliate with the underlying intermediate filaments via linker proteins to provide mechanical strength to epithelia. In the present study, we generated an antibody, AH12.2, that recognizes Dsg2. We show that Dsg2 but not another desmosomal cadherin, Dsc2, is cleaved by cysteine proteases during the onset of intestinal epithelial cell (IEC) apoptosis. Small interfering RNA-mediated down-regulation of Dsg2 protected epithelial cells from apoptosis. Moreover, we report that a C-terminal fragment of Dsg2 regulates apoptosis and Dsg2 protein levels. Our studies highlight a novel mechanism by which Dsg2 regulates IEC apoptosis driven by cysteine proteases during physiological differentiation and inflammation.

These authors contributed equally to this work.

Address correspondence to: Asma Nusrat (anusrat{at}emory.edu)

Abbreviations used: TJ, tight junction; AJ, adherens junction; Dsg2, desmoglein-2; tDsg2, truncated Dsg2; Dsc2, desmocollin-2; DSP, desmoplakin; Pg, plakoglobin; DM, desmosome; IEC, intestinal epithelial cell; PARP, poly(ADP-ribose) polymerase; Camp, camptothecin.

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