TY - JOUR
T1 - Intestinal amino acid availability via PEPT-1 affects TORC1/2 signaling and the unfolded protein response
AU - Geillinger, Kerstin E.
AU - Kuhlmann, Katja
AU - Eisenacher, Martin
AU - Giesbertz, Pieter
AU - Meyer, Helmut E.
AU - Daniel, Hannelore
AU - Spanier, Britta
PY - 2014/8/1
Y1 - 2014/8/1
N2 - The intestinal peptide transporter PEPT-1 plays an important role in development, growth, reproduction, and stress tolerance in Caenorhabditis elegans, as revealed by the severe phenotype of the pept-1-deficient strain. The reduced number of offspring and increased stress resistance were shown to result from changes in the insulin/IGF-signaling cascade. To further elucidate the regulatory network behind the phenotypic alterations in PEPT1-deficient animals, a quantitative proteome analysis combined with transcriptome profiling was applied. Various target genes of XBP-1, the major mediator of the unfolded protein response, were found to be downregulated at the mRNA and protein levels, accompanied by a reduction of spliced xbp-1 mRNA. Proteome analysis also revealed a markedly reduced content of numerous ribosomal proteins. This was associated with a reduction in the protein synthesis rate in pept-1 C. elegans, a process that is strictly regulated by the TOR (target of rapamycine) complex, the cellular sensor for free amino acids. These data argue for a central role of PEPT-1 in cellular amino acid homeostasis. In PEPT-1 deficiency, amino acid levels dropped systematically, leading to alterations in protein synthesis and in the IRE-1/XBP-1 pathway.
AB - The intestinal peptide transporter PEPT-1 plays an important role in development, growth, reproduction, and stress tolerance in Caenorhabditis elegans, as revealed by the severe phenotype of the pept-1-deficient strain. The reduced number of offspring and increased stress resistance were shown to result from changes in the insulin/IGF-signaling cascade. To further elucidate the regulatory network behind the phenotypic alterations in PEPT1-deficient animals, a quantitative proteome analysis combined with transcriptome profiling was applied. Various target genes of XBP-1, the major mediator of the unfolded protein response, were found to be downregulated at the mRNA and protein levels, accompanied by a reduction of spliced xbp-1 mRNA. Proteome analysis also revealed a markedly reduced content of numerous ribosomal proteins. This was associated with a reduction in the protein synthesis rate in pept-1 C. elegans, a process that is strictly regulated by the TOR (target of rapamycine) complex, the cellular sensor for free amino acids. These data argue for a central role of PEPT-1 in cellular amino acid homeostasis. In PEPT-1 deficiency, amino acid levels dropped systematically, leading to alterations in protein synthesis and in the IRE-1/XBP-1 pathway.
KW - Caenorhabditis elegans
KW - PEPT-1
KW - TOR
KW - XBP-1
KW - unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=84905371727&partnerID=8YFLogxK
U2 - 10.1021/pr5002669
DO - 10.1021/pr5002669
M3 - Article
C2 - 24999909
AN - SCOPUS:84905371727
SN - 1535-3893
VL - 13
SP - 3685
EP - 3692
JO - Journal of Proteome Research
JF - Journal of Proteome Research
IS - 8
ER -