In the endoplasmic reticulum (ER), the translocation-associated protein complex (TRAP), also called signal sequence receptor (SSR), includes four integral membrane proteins TRAPĪ±/SSR1, TRAPĪ²/SSR2, and TRAPĪ“/SSR4 with the bulk of their extramembranous portions primarily in the ER lumen, whereas the extramembranous portion of TRAPĪ³/SSR3 is primarily cytosolic. Individually diminished expression of either TRAPĪ±/SSR1, TRAPĪ²/SSR2, or TRAPĪ“/SSR4 mRNA is known in each case to lower TRAPĪ±/SSR1 protein levels, leading to impaired proinsulin biosynthesis, whereas forced expression of TRAPĪ±/SSR1 at least partially suppresses the proinsulin biosynthetic defect. Here, we report that diminished TRAPĪ³/SSR3 expression in pancreatic Ī²-cells leaves TRAPĪ±/SSR1 levels unaffected while nevertheless inhibiting cotranslational and posttranslational translocation of preproinsulin into the ER. Crucially, acute exposure to high glucose leads to a rapid upregulation of both TRAPĪ³/SSR3 and proinsulin protein without change in the respective mRNA levels, as observed in cultured rodent Ī²-cell lines and confirmed in human islets. Strikingly, pancreatic Ī²-cells with suppressed TRAPĪ³/SSR3 expression are blocked in glucose-dependent upregulation of proinsulin (or insulin) biosynthesis. Most remarkably, overexpression of TRAPĪ³/SSR3 in control Ī²-cells raises proinsulin levels, even without boosting extracellular glucose. The data suggest the possibility that TRAPĪ³/SSR3 may fulfill a rate-limiting function in preproinsulin translocation across the ER membrane for proinsulin biosynthesis.
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