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

Abstract

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.

Physiological Starvation PromotesCaenorhabditis elegansVulval Induction

“…Of note, however, neither pept-1(lg601) or rsks-1(ok1255) single mutants exhibited vulval hyperinduction or other vulval defects (N > 300/strain). As compromised PEPT-1 activity leads to strongly nutrient-deprived animals, even in a food-rich environment (Meissner et al 2004; Geillinger et al 2014), these results are further consistent with our observation that sensory perception of external starvation conditions is not required to increase vulval induction of lin-3(rf) animals (Table 1). …”

Taste and move: glucose and peptide transporters in the gastrointestinal tract

“…Proteome analysis performed in animals lacking PEPT1 revealed a drastically reduced rate of protein synthesis (Geillinger et al . ). The developmental retardation was shown to involve germline signalling (Spanier et al .…”

Identification of key pathways and metabolic fingerprints of longevity in C. elegans

“…The substrates of these dehydrogenases remain unclear, although SODH-1 has been reported to catalyze the breakdown of ethanol 22 . In addition, SODH-1 was predicted to have oxidoreductase function and its expression can be regulated by several essential metabolic genes, including daf-16 (FOXO), lbp-5 (lipid binding protein), mdt-15 (mediator subunit), and pept-1 (peptide transporter) [23][24][25] . Hence, the known biological activity of SODH-1 may include more than its function in fermentative metabolism alone.…”