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The Death Domain of Kidney Ankyrin Interacts with Fas and Promotes Fas-Mediated Cell Death in Renal Epithelia

Marcela Del Rio^*, Abubakr Imam^*, Maryely DeLeon^*, Gary Gomez^*, Jaya Mishra, Qing Ma, Samir Parikh and Prasad Devarajan^*,

*Department of Nephrology, Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, and Department of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.

Correspondence to Dr. Prasad Devarajan, Nephrology and Hypertension, MLC 7022, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. Phone: 513-636-4531; Fax: 513-636-7407;

ABSTRACT. Ankyrins are a ubiquitously expressed family of conserved proteins that mediate the linkage of integral membrane proteins such as transporters and channels with the underlying cytoskeleton. Ankyrins possess a conserved death domain, the functional significance of which has remained puzzling. In this study, the death domain of AnkG190, the isoform of ankyrin expressed in kidney tubules, was used as bait in a yeast two-hybrid screen to identify interacting partners. One of these interactions was with the proapoptotic molecule Fas. This was confirmed by coimmunoprecipitation, colocalization, and glutathione S-transferase pull-down assays in cultured renal epithelial (MDCK) cells. Site-directed mutagenesis of a conserved arginine (R1496 in AnkG190), previously shown to be critical for the binding of Fas (R234 in Fas) to FADD, abolished the interaction of ankyrin’s death domain with Fas. Overexpression of constructs containing ankyrin’s death domain promoted Fas-mediated apoptosis in MDCK cells. The linkage between ankyrin and Fas was confirmed in vivo in mouse kidney tubule cells by coimmunoprecipitation and colocalization. In an established mouse model of renal ischemia-reperfusion injury characterized by apoptotic tubule cell death, the expression of both ankyrin and Fas was markedly induced, and the interaction between these molecules remained intact. The results identify a novel tethering interaction between ankyrin and Fas in kidney epithelia and suggest that AnkG190 may play a role as an adapter molecule in renal tubule cell death. E-mail: prasad.devarajan@cchmc.org.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673