Insulin-like signaling pathways have conserved functions in controlling development and aging. In C. elegans, the DAF-2 insulin-like signaling pathway controls dauer arrest and longevity by regulating the FoxO transcription factor DAF-16. Although initial screens for DAF-2 signaling components appear to have been saturated, recent sensitized screens indicate that new regulators of DAF-2 signaling remain to be discovered.We have shown that the conserved protein EAK-7 acts in parallel with AKT-1 to prevent dauer arrest by inhibiting DAF-16/FoxO. In a screen for suppressors of
eak-7;
akt-1 dauer arrest (seak screen), we isolated a strain with a 3.5 kb deletion on chromosome I, dpDf665, that cosegregated with the seak phenotype. dpDf665 deletes portions of two genes, including
trap-1, which encodes the C. elegans ortholog of mammalian SSR1 (signal sequence receptor 1). In vitro, SSR1 acts in a heterotetrameric complex with SSR2, SSR3, and SSR4 to promote the cotranslational translocation of a subset of secreted proteins into the endoplasmic reticulum (ER). However, the physiological function of SSR1 is obscure.
trap-1/SSR1 null mutants suppressed
eak-7;
akt-1 dauer arrest to the same extent as dpDf665, indicating that dpDf665 suppresses dauer arrest due to loss of
trap-1/SSR1 activity.
trap-1/SSR1 mutation suppressed the dauer-constitutive phenotype of
daf-2(
e1368) but did not influence dauer arrest in mutants with reduced DAF-7/TGFb or DAF-9/dafachronic acid pathway activity, indicating that TRAP-1/SSR1 normally functions to promote dauer arrest through the DAF-2 insulin-like pathway. Nonsense mutations in
trap-2 and
trap-3, which encode orthologs of mammalian SSR2 and SSR3, suppressed
daf-2(
e1368) dauer arrest to the same extent as
trap-1/SSR1 mutation, suggesting that TRAP-1 acts as part of a conserved TRAP complex to control DAF-2 insulin-like signaling. A functional TRAP-1::mCherry fusion protein was expressed in most tissues and exhibited a reticular pattern of localization consistent with ER localization. Intriguingly,
trap-1/SSR1 mutation suppresses the dauer-constitutive phenotype of a subset of
daf-2 mutant alleles. Taken together, our data suggest that TRAP-1/SSR1 may regulate DAF-2 insulin-like signaling by controlling the activity of insulin-like peptides. Our findings provide the first evidence that TRAP-1/SSR1 controls the activity of a specific signaling pathway in vivo..