Requirement for TRanslocon-Associated Protein (TRAP) α in insulin biogenesis

The mechanistic basis for the biogenesis of peptide hormones and growth factors is poorly understood. Here we show that the conserved endoplasmic reticulum (ER) membrane translocon-associated protein (TRAP) α, also known as signal sequence receptor 1 (SSR1), plays a critical role in the biosynthesis of insulin. A genetic screen in the nematode Caenorhabditis elegans revealed trap-1, which encodes the C. elegans TRAPα ortholog, as a modifier of DAF-2 insulin receptor (InsR) signaling. Genetic analysis indicates that TRAP-1 acts upstream of DAF-2/InsR to control C. elegans development. Endogenous C. elegans TRAP-1 and mammalian TRAPα both localized to the ER. In pancreatic beta cells, TRAPα deletion impaired preproinsulin translocation but did not affect the synthesis of α1-antitrypsin, indicating that TRAPα selectively influences the translocation of a subset of secreted proteins. Surprisingly, loss of TRAPα function also resulted in disruption of distal steps in insulin biogenesis including proinsulin processing and secretion. These results show that TRAPα assists in the ER translocation of preproinsulin and unveil unanticipated additional consequences of TRAPα loss-of-function on the intracellular trafficking and maturation of proinsulin. The association of common intronic single nucleotide variants in the human TRAPα gene with susceptibility to Type 2 diabetes and pancreatic beta cell dysfunction suggests that impairment of preproinsulin translocation and proinsulin trafficking may contribute to the pathogenesis of Type 2 diabetes.