Intestinal Amino Acid Availability via PEPT‑1 Affects TORC1/2 Signaling and the Unfolded Protein Response

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.