Role of Sec61α2 Translocon in Insulin Biosynthesis.

Autor: Xu X; Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI.; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China., Bell TW; Department of Chemistry, University of Nevada, Reno, NV., Le T; Department of Chemistry, University of Nevada, Reno, NV., Zhao I; Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI., Walker E; Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI., Wang Y; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China., Xu N; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China., Soleimanpour SA; Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI., Russ HA; Diabetes Institute, University of Florida College of Medicine, Gainesville, FL., Qi L; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA., Tsai B; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI., Liu M; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China., Arvan P; Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI.
Jazyk: angličtina
Zdroj: Diabetes [Diabetes] 2024 Dec 01; Vol. 73 (12), pp. 2034-2044.
DOI: 10.2337/db24-0115
Abstrakt: Translocational regulation of proinsulin biosynthesis in pancreatic β-cells is unknown, although several studies have reported an important accessory role for the Translocon-Associated Protein complex to assist preproinsulin delivery into the endoplasmic reticulum via the heterotrimeric Sec61 translocon (comprising α, β, and γ subunits). The actual protein-conducting channel is the α-subunit encoded either by Sec61A1 or its paralog Sec61A2. Although the underlying channel selectivity for preproinsulin translocation is unknown, almost all studies of Sec61α to date have focused on Sec61α1. There is currently no evidence to suggest that this gene product plays a major role in proinsulin production, whereas genome-wide association studies indicate linkage of Sec61A2 with diabetes. Here, we report that evolutionary differences in mouse preproinsulin signal peptides affect proinsulin biosynthesis. Moreover, we find that, although some preproinsulin translocation can proceed through Sec61α1, Sec61α2 has a greater impact on proinsulin biosynthesis in pancreatic β-cells. Remarkably, Sec61α2 translocon deficiency exerts a significant inhibitory effect on the biosynthesis of preproinsulin itself, including a disproportionate increase of full-length nascent chain unreleased from ribosomes. This study not only reveals novel translocational regulation of proinsulin biosynthesis but also provides a rationale for genetic evidence suggesting an important role of Sec61α2 in maintaining blood glucose homeostasis.
(© 2024 by the American Diabetes Association.)
Databáze: MEDLINE