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Abstract
Mounting evidence suggests a role for alternative splicing (AS) of transcripts in the normal physiology and pathophysiology of the pancreatic β-cell. In the apparent absence of RNA repair systems, RNA decay pathways are likely to play an important role in controlling the stability, distribution and diversity of transcript isoforms in these cells. Around 35% of alternatively spliced transcripts in human cells contain premature termination codons (PTCs) and are targeted for degradation via nonsense-mediated decay (NMD), a vital quality control process. Inflammatory cytokines, whose levels are increased in both type 1 (T1D) and type 2 (T2D) diabetes, stimulate alternative splicing events and the expression of NMD components, and may or may not be associated with the activation of the NMD pathway. It is, however, now possible to infer that NMD plays a crucial role in regulating transcript processing in normal and stress conditions in pancreatic β-cells. In this review, we describe the possible role of Regulated Unproductive Splicing and Translation (RUST), a molecular mechanism embracing NMD activity in relationship to AS and translation of damaged transcript isoforms in these cells. This process substantially reduces the abundance of non-functional transcript isoforms, and its dysregulation may be involved in pancreatic β-cell failure in diabetes.
Highlights
Diabetes mellitus currently affects ~460 m adults worldwide and its incidence is expected to exceed 700 m by 2045 [1]
This study revealed that nitroxidative stress is mechanistically involved in cytokine-mediated up-regulation of nonsense-mediated decay (NMD) components, since chemical inhibition of inducible nitric oxide by N-methyl-L-argenine (NMA), normalized cytokine upregulation of the NMD components in INS-1 cells [7]
Knowing that pro-inflammatory cytokines regulate alternative splicing events and the NMD pathway in human and rodent primary b-cells [9, 28, 37, 40, 41], we propose a model (Figure 4) in which incomplete Regulated Unproductive Splicing and Translation (RUST) leads to accumulation of unproductive transcripts whose translation into unfolded, truncated polypeptides overwhelms ER capacity and drives unresolved ER stress
Summary
Diabetes mellitus currently affects ~460 m adults worldwide and its incidence is expected to exceed 700 m by 2045 [1]. A major regulator of pancreatic b-cell function [31], strongly affects insulin gene expression, biosynthesis, and secretion, through multiple mechanisms including changes in transcription, pre-mRNA alternative splicing, translation and mRNA stability [32,33,34]. The circadian clock has recently been shown to modulate synchronicity of insulin secretion in dark-light phases by regulating the alternative splicing of pre-mRNAs coding for proteins involved in insulin biosynthesis and exocytosis in primary mouse b-cells. The human NMD machinery is complex and involves multiple proteins including Upf, Upf, Upf3a, Upf3b, Smg, Smg, Smg, And Smg (See Table 2) Together, these are responsible for the detection and decay of PTC-containing transcripts (Figure 2A). 56 RENT3B, UPF3X shuttling to nucleus, but mainly in cytoplasm shuttling to nucleus, but mainly in cytoplasm
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