posted on 2021-12-02, 16:31authored byXiaoxi Xu, Yumeng Huang, Xin Li, Peter Arvan, Ming Liu
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 co-translational
and post-translational 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 — 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 remarkable,
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.
Funding
This collaborative work was supported in the USA by NIH R01-DK111174 and R01-DK48280 and in China by the National Key R&D Program 2019YFA0802502; the National Natural Science Foundation of China 81620108004, 81830025, and 81700699; and support from the Tianjin Municipal Science and Technology Commission (17ZXMFSY00150 and 18JCQNJC82100).