Requirement for translocon-associated protein (TRAP) α in insulin biogenesis

Xin Li, Omar A. Itani, Leena Haataja, Kathleen J. Dumas, Jing Yang, Jeeyeon Cha, Stephane Flibotte, Hung Jen Shih, Colin E. Delaney, Jialu Xu, Ling Qi, Peter Arvan, Ming Liu, Patrick J. Hu

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Abstract

The mechanistic basis for the biogenesis of peptide hormones and growth factors is poorly understood. Here, we show that the conserved endoplasmic reticulum membrane translocon-associated protein α (TRAPα), also known as signal sequence receptor 1, plays a critical role in the biosynthesis of insulin. Genetic analysis in the nematode Caenorhabditis elegans and biochemical studies in pancreatic β cells reveal that TRAPα deletion impairs preproinsulin translocation while unexpectedly disrupting distal steps in insulin biogenesis including proinsulin processing and secretion. The association of common intronic single-nucleotide variants in the human TRAPα gene with susceptibility to type 2 diabetes and pancreatic β cell dysfunction suggests that impairment of preproinsulin translocation and proinsulin trafficking may contribute to the pathogenesis of type 2 diabetes.

Original languageEnglish
Article numbereaax0292
JournalScience Advances
Volume5
Issue number12
DOIs
StatePublished - Dec 4 2019
Externally publishedYes

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    Li, X., Itani, O. A., Haataja, L., Dumas, K. J., Yang, J., Cha, J., Flibotte, S., Shih, H. J., Delaney, C. E., Xu, J., Qi, L., Arvan, P., Liu, M., & Hu, P. J. (2019). Requirement for translocon-associated protein (TRAP) α in insulin biogenesis. Science Advances, 5(12), [eaax0292]. https://doi.org/10.1126/sciadv.aax0292