Role of Sec61a2 translocon in insulin biosynthesis

<p dir="ltr"><b>Abstract</b></p><p dir="ltr">Translocational regulation of proinsulin biosynthesis in pancreatic b-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 a, b, and g subunits). The actual protein-conducting channel is the a-subunit encoded either by <i>Sec61A1</i> or its paralog <i>Sec61A2.</i><i> </i>Although the underlying channel selectivity for preproinsulin translocation is unknown, almost all studies of Sec61a to date have focused on Sec61a1. 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 <i>Sec61A2</i> 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 Sec61a1, Sec61a2 has a greater impact on proinsulin biosynthesis in pancreatic b-cells. Remarkably, Sec61a2-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 Sec61a2 in maintaining blood glucose homeostasis.</p><p><br></p><p dir="ltr"><b>Article Highlights</b></p><p dir="ltr">· Preproinsulin uses its signal peptide to engage the Sec61 translocon, but surprisingly, existing data show no appreciable insulin biosynthesis or diabetes phenotypes linked to the Sec61A1 gene.</p><p dir="ltr">· We wanted to know if Sec61a2 might contribute to insulin biosynthesis, because GWAS links Sec61A2 (the unstudied paralog of Sec61A1) to T2D.</p><p dir="ltr">· We found a major drop in proinsulin biosynthesis in b-cells deficient for Sec61a2 (much more than for Sec61a1) and further, this reflexively inhibits preproinsulin translation. </p><p dir="ltr">Our data suggest that the genetic linkage of Sec61A2 to T2D may be explained by a defect in insulin biosynthesis.</p>