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J. Biol. Chem., Vol. 279, Issue 35, 36739-36745, August 27, 2004

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Deletion of the Intestinal Peptide Transporter Affects Insulin and TOR Signaling in Caenorhabditis elegans^*

Barbara Meissner, Michael Boll, Hannelore Daniel¶, and Ralf Baumeister||**

From the Adolph-Butenandt-Institute/Molecular Neurogenetics, Ludwig-Maximilians-University of Munich, D-80336 Munich, Germany, Molecular Nutrition Unit, Technical University of Munich, D-85350 Freising-Weihenstephan, Germany, and ^||Bio3, Bioinformatics and Molecular Genetics, University of Freiburg, D-79104 Freiburg, Germany

The mammalian intestinal peptide transporter PEPT1 mediates the uptake of di- and tripeptides from the gut lumen into intestinal epithelial cells and acts in parallel with amino acid transporters. Here we address the importance of the PEPT1 orthologue PEP-2 for the assimilation of dietary protein and for overall protein nutrition in Caenorhabditis elegans. pep-2 is expressed specifically along the apical membrane of the intestinal cells, and in pep-2 deletion mutant animals, uptake of intact peptides from the gut lumen is abolished. The consequences are a severely retarded development, reduced progeny and body size, and increased stress tolerance. We show here that pep-2 cross-talks with both the C. elegans target of rapamycin (TOR) and the DAF-2/insulin-signaling pathways. The pep-2 mutant enhances the developmental and longevity phenotypes of daf-2, resulting, among other effects, in a pronounced increase in adult life span. Moreover, all aspects of a weak let-363/TOR RNA interference phenotype are intensified by pep-2 deletion, indicating that pep-2 function upstream of TOR-mediated nutrient sensing. Our findings provide evidence for a predominant role of the intestinal peptide transporter for the delivery of bulk quantities of amino acids for growth and development, which consequently affects signaling pathways that regulate metabolism and aging.

Received for publication, March 29, 2004 , and in revised form, May 19, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a grant from the Else-Kroener-Fresenius Foundation.

^** Supported by grants from the European Community, the Verum Foundation, and the Fonds der Chemischen Industrie. To whom correspondence should be addressed: Bio3/Bioinformatics and Molecular Genetics, Schaenzlestr. 1, D-79104 Freiburg, Germany. Tel.: 49-761-203-2799; Fax: 49-761-203-8351; E-mail: baumeister{at}celegans.de.

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