Regulation of β-cell function by RNA-binding proteins

Abstract

β-cells of the pancreatic islets are highly specialized and high-throughput units for the production of insulin, the key hormone for maintenance of glucose homeostasis. Elevation of extracellular glucose and/or GLP-1 levels triggers a rapid upregulation of insulin biosynthesis through the activation of post-transcriptional mechanisms. RNA-binding proteins are emerging as key factors in the regulation of these mechanisms as well as in other aspects of β-cell function and glucose homeostasis at large, and thus may be implicated in the pathogenesis of diabetes. Here we review current research in the field, with a major emphasis on RNA-binding proteins that control biosynthesis of insulin and other components of the insulin secretory granules by modulating the stability and translation of their mRNAs.

Keywords: Diabetes; Insulin; RNA-binding proteins; Translation; mRNA stability; β-cells.

Figure 1

Regulatory elements in the preproinsulin mRNA UTRs. The green boxes indicate a 29 bp-sequence element, identified in the 5′-UTR of the rat preproinsulin gene 1. This element partially overlaps with the 9 bp-sequence identified in the rat proinsulin 2 mRNA as the preproinsulin glucose element (ppIGE, in yellow). The 3′-UTR of the preproinsulin transcript contains elements that control mRNA stability, including a pyrimidine-rich tract (in blue) downstream of the coding sequence (CDS), and a UUGAA motif (in orange). The UUGAA element is identical in human, rat and mouse, while other regulatory elements within preproinsulin mRNAs, though highly conserved in their location, display various degrees of sequence homology. The cross-species sequence homology of these elements among rat, mouse and human preproinsulin transcripts is shown. Red arrows point to non-conserved nucleotides. The shaded sequences are those identified as PTBP1 binding sites. A polypyrimidine tract is also found in the 5′-UTR of the human preproinsulin mRNA (not shown).

Figure 2

Model of RBP function in insulin expression and SG biosynthesis. Coordinated regulation by RBPs maintains insulin SG stores adequate to metabolic needs. Cytosolic RBPs with positive (PTBP1, PABP/PDI) and negative (HuD and hnRNP K) roles on insulin translation, and thereby SG biosynthesis, are outlined in black and red, respectively. Stimulation of β-cells induces cytoplasmic accumulation of PTBP1 through two distinct pathways. GLP-1 elevates intracellular cAMP levels, thereby activating PKA, which phosphorylates PTBP1 and thus prompts its redistribution into the cytoplasm. Glucose also triggers the cytosolic accumulation of PTBP1 through a phosphorylation-independent mechanism. In the cytoplasm PTBP1 binds to consensus sequences in the 5′- and 3′-UTRs of mRNAs encoding insulin and other proteins of the SGs. Glucose promotes the PABP-mediated binding of PDI to preproinsulin mRNA, whereas it inhibits that of HuD.