1. The Role of TRAPγ/SSR3 in Preproinsulin Translocation Into the Endoplasmic Reticulum.
- Author
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Xu, Xiaoxi, Huang, Yumeng, Li, Xin, Arvan, Peter, and Liu, Ming
- Subjects
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ENDOPLASMIC reticulum , *MEMBRANE proteins , *PROINSULIN , *BIOSYNTHESIS , *RESEARCH , *BIOLOGICAL transport , *ANIMAL experimentation , *RESEARCH methodology , *CELL receptors , *PROTEIN precursors , *RABBITS , *EVALUATION research , *MEMBRANE glycoproteins , *INSULIN , *ISLANDS of Langerhans , *RATS , *GENE expression , *COMPARATIVE studies , *CALCIUM-binding proteins , *GENETIC techniques , *CELL lines , *EPITHELIAL cells , *CYTOPLASM , *MICE - Abstract
In the endoplasmic reticulum (ER), the translocation-associated protein complex (TRAP), also called signal sequence receptor (SSR), includes four integral membrane proteins TRAPα/SSR1, TRAPβ/SSR2, and TRAPδ/SSR4 with the bulk of their extramembranous portions primarily in the ER lumen, whereas the extramembranous portion of TRAPγ/SSR3 is primarily cytosolic. Individually diminished expression of either TRAPα/SSR1, TRAPβ/SSR2, or TRAPδ/SSR4 mRNA is known in each case to lower TRAPα/SSR1 protein levels, leading to impaired proinsulin biosynthesis, whereas forced expression of TRAPα/SSR1 at least partially suppresses the proinsulin biosynthetic defect. Here, we report that diminished TRAPγ/SSR3 expression in pancreatic β-cells leaves TRAPα/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 TRAPγ/SSR3 and proinsulin protein without change in the respective mRNA levels, as observed in cultured rodent β-cell lines and confirmed in human islets. Strikingly, pancreatic β-cells with suppressed TRAPγ/SSR3 expression are blocked in glucose-dependent upregulation of proinsulin (or insulin) biosynthesis. Most remarkably, overexpression of TRAPγ/SSR3 in control β-cells raises proinsulin levels, even without boosting extracellular glucose. The data suggest the possibility that TRAPγ/SSR3 may fulfill a rate-limiting function in preproinsulin translocation across the ER membrane for proinsulin biosynthesis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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