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 (comprised of 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 nacent 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.

中文翻译：

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Sec61α2 转位子在胰岛素生物合成中的作用


胰腺 β 细胞中胰岛素原生物合成的易位调节尚不清楚，尽管几项研究报道了转位蛋白复合物的重要辅助作用，以协助胰岛素原通过异源三聚体 Sec61 转基因（由 α、β 和 γ 亚基组成）递送到内质网中。实际的蛋白质传导通道是由 Sec61A1 或其旁系同源物 Sec61A2 编码的 α 亚基。尽管胰岛素原易位的潜在通道选择性尚不清楚，但迄今为止几乎所有关于 Sec61α 的研究都集中在 Sec61α1 上。目前没有证据表明该基因产物在胰岛素原产生中起主要作用，而全基因组关联研究表明 Sec61A2 与糖尿病有关。在这里，我们报道了小鼠胰岛素原信号肽的进化差异会影响胰岛素原的生物合成。此外，我们发现虽然一些胰岛素原易位可以通过 Sec61α1 进行，但 Sec61α2 对胰腺 β 细胞中胰岛素原的生物合成有更大的影响。值得注意的是，Sec61α2-转位子缺陷对胰岛素原本身的生物合成产生显着的抑制作用，包括核糖体未释放的全长新生链不成比例的增加。这项研究不仅揭示了胰岛素原生物合成的新型易位调节，而且还为表明 Sec61α2 在维持血糖稳态中的重要作用的遗传证据提供了理论依据。