Involvement of the RNA-binding protein ARE/poly(U)-binding factor 1 (AUF1) in the cytotoxic effects of proinflammatory cytokines on pancreatic beta cells

Abstract

Aims/hypothesis Chronic exposure of pancreatic beta cells to proinflammatory cytokines leads to impaired insulin secretion and apoptosis. ARE/poly(U)-binding factor 1 (AUF1) belongs to a protein family that controls mRNA stability and translation by associating with adenosine-and uridine-rich regions of target messengers. We investigated the involvement of AUF1 in cytokine-induced beta cell dysfunction. Methods Production and subcellular distribution of AUF1 isoforms were analysed by western blotting. To test for their role in the control of beta cell functions, each isoform was overproduced individually in insulin-secreting cells. The contribution to cytokine-mediated beta cell dysfunction was evaluated by preventing the production of AUF1 isoforms by RNA interference. The effect of AUF1 on the production of potential targets was assessed by western blotting. Results MIN6 cells and human pancreatic islets were found to produce four AUF1 isoforms (p42>p45>p37>p40). AUF1 isoforms were mainly localised in the nucleus but were partially translocated to the cytoplasm upon exposure of beta cells to cytokines and activation of the ERK pathway. Overproduction of AUF1 did not affect glucose-induced insulin secretion but promoted apoptosis. This effect was associated with a decrease in the production of the antiapoptotic proteins, B cell leukaemia/lymphoma 2 (BCL2) and myeloid cell leukaemia sequence 1 (MCL1). Silencing of AUF1 isoforms restored the levels of the anti-apoptotic proteins, attenuated the activation of the nuclear factor-κB (NFκB) pathway, and protected the beta cells from cytokineinduced apoptosis. Conclusions/interpretation Our findings point to a contribution of AUF1 to the deleterious effects of cytokines on beta cell functions and suggest a role for this RNA-binding protein in the early phases of type 1 diabetes.

Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53-dependent pathway

“…Chronic exposure to inflammatory conditions leads to beta cell dysfunction and apoptosis [32,44,45]. A recent investigation has revealed that the level of miR-34a increased concomitantly in cytokinetreated MIN6 cells and human pancreatic islets, and contributed to beta cell dysfunction [32].…”

Post-transcriptional regulation in metabolic diseases

“…47 ARE/ poly(U)-binding factor 1 (AUF1), the best-characterized RBP that controls mRNA stability and translation by associating with AU-or U-rich sequence elements (ARE) frequently found within the 3'-UTR, was found to be involved in the cytotoxic effects of proinflammatory cytokines on pancreatic β cells. 48 Exposure of pancreatic β-cells to cytokines caused translocalization of (PI3K), phosphoinositide-dependent kinase 1 (PDK1) and the protein kinase AKT, and thereby regulates not only glucose and lipid metabolism but also cellular proliferation and apoptosis. [15][16][17][18][19][20][21][22][23] Indeed, studies of animal models with targeted mutations in genes that encode mediators of insulin signaling have revealed that insulin signaling plays a central role in metabolic actions in insulin-sensitive tissues and contributes to the pathogenesis of T2DM.…”

Is ARE/poly(U)-binding factor 1 (AUF1) a new player in cytokine-mediated beta cell apoptosis?

“…Roggli and co-workers observed that MIN6 cells and human islets produce all the different AUF1 isoforms [37]. Exposure of MIN6 cells to cytokines induces their translocation from the nucleus to the cytosol, indicating their activation.…”

“…Identification of novel molecules that modulate this cell death pathway will hopefully provide alternative approaches to prevent beta cell apoptosis in early type 1 diabetes. In this issue of Diabetologia, Roggli and colleagues investigated the role of the RNA binding protein ARE/poly(U)-binding factor 1 (AUF1) on cytokine-mediated beta cell apoptosis [37]. This protein interacts specifically with adenosine-and uridinerich elements (ARE) located in the 3′ untranslated region (UTR) of target mRNAs, thus regulating their stability [38].…”

“…The blue arrows represent induction and the red lines represent inhibition. The dotted lines indicate that the role of AUF1 in the regulation of these proteins is yet to be fully elucidated and may be indirect (Ccl2)/MCP1 chemokines in MIN6 cells [37]. The authors showed that cytokine-mediated AUF1 activation in beta cells is downstream of ERK.…”