RT Journal Article
SR Electronic
T1 Requirement for TRanslocon-Associated Protein (TRAP) α in insulin biogenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 531491
DO 10.1101/531491
A1 Xin Li
A1 Omar A. Itani
A1 Leena Haataja
A1 Kathleen J. Dumas
A1 Jing Yang
A1 Jeeyeon Cha
A1 Stephane Flibotte
A1 Hung-Jen Shih
A1 Jialu Xu
A1 Ling Qi
A1 Peter Arvan
A1 Ming Liu
A1 Patrick J. Hu
YR 2019
UL http://biorxiv.org/content/early/2019/01/26/531491.abstract
AB 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)1, 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 dysfunction2 suggests that impairment of preproinsulin translocation and proinsulin trafficking may contribute to the pathogenesis of Type 2 diabetes.