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bioRxiv · 10.1101/2024.06.26.599433

Post-transcriptional regulation by the CCR4-NOT deadenylase complex maintains redox homeostasis in insulin biosynthesis in mouse pancreatic β cells

Yanagiya, A.·Stoney, P. N.·Tara, Y.·Takaoka, S.·Vares, G.·Higa, R.·Friedman, N. R.·Villar-Briones, A.·Yamamoto, T.
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Abstract

Pancreatic {beta} cells synthesize insulin to maintain glucose homeostasis. In diabetes, elevated blood glucose and insulin resistance compel {beta} cells to produce insulin, and hence {beta} cells are vulnerable to oxidative stress by glucotoxicity. In insulin biosynthesis, the conversion of proinsulin to insulin is initiated by forming disulfide bonds in proinsulin for oxidative protein folding. Insulin content and insulin secretion in {beta} cells are decreased by deletion of CNOT7, a catalytic subunit of the CCR4-NOT complex, and accompanied by increased proinsulin, implying the impaired conversion of proinsulin to insulin. We found that PRDX4 essential for disulfide bond formation in proinsulin, is reduced in Cnot7-KO {beta} cells. Moreover, protein expression of CNOT8, a paralog of CNOT7, is increased in Cnot7-KO {beta} cells and binds to Prdx4 mRNA via MSI2. Here, we demonstrate the post-transcriptional regulation of Prdx4 mRNA by the CCR4-NOT complex to maintain oxidative-reductive homeostasis in insulin biosynthesis. HIGHLIGHTSO_LIInsulin content and secretion are decreased in Cnot7-KO pancreatic {beta} cells. C_LIO_LIPRDX4, needed for proinsulin folding, is decreased in Cnot7-KO pancreatic islets. C_LIO_LIThe conversion of proinsulin to insulin is impaired in Cnot7-KO {beta} cells. C_LIO_LICNOT8, but not CNOT7, interacts with MSI2 that binds to Prdx4 mRNA C_LI

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Yanagiya, A., Stoney, P. N., Tara, Y., Takaoka, S., Vares, G., Higa, R., Friedman, N. R., Villar-Briones, A., Yamamoto, T.. 2024-06-29. Post-transcriptional regulation by the CCR4-NOT deadenylase complex maintains redox homeostasis in insulin biosynthesis in mouse pancreatic β cells. https://doi.org/10.1101/2024.06.26.599433

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