PERK in the life and death of the pancreatic β-cell

To ensure cellular survival to ER (endoplasmic reticulum) stress, PERK [PKR (double-stranded-RNA-dependent protein kinase)-like ER kinase], an ER transmembrane kinase, is activated as part of the unfolded protein response. PERK is highly expressed in pancreatic β-cells and is essential in the β-cell’s development, differentiation and function. However, chronic activation of PERK can induce cell death, and its activation has been implicated in both Type 1 and Type 2 diabetes. This short review aims to provide an insight into our current understanding of the role of PERK in the life and death of the β-cell. Introduction The β-cell’s primary function is to synthesize and secrete insulin in response to glucose in order to maintain normoglycaemia. This places a huge demand on the β-cell’s highly developed ER (endoplasmic reticulum) to synthesize, fold and process large quantities of insulin. Failure of the ER to cope with this demand would result in the accumulation of unfolded proteins, ER stress, decreased β-cell function and ultimately cell death. In order to alleviate ER stress and promote cell survival, an adaptive response, known as the UPR (unfolded protein response), is activated, resulting in decreased ER folding load, increased ER folding capacity and the clearance of misfolded proteins from the ER (reviewed in [1]). Transducers of this UPR, which are highly expressed in β-cells, include three ER transmembrane proteins: PERK [PKR (double-stranded-RNA-dependent protein kinase)like ER kinase], IRE1 (inositol requiring enzyme-1) [an endonuclease required for the splicing and activation of XBP-1 (X-box-binding protein-1)] and ATF6 (activating transcription factor-6) (see Figure 1a). PERK phosphorylates the α-subunit of eIF2α (eukaryotic initiation factor-2α), which inhibits protein synthesis and hence decreases ER protein folding load. Moreover, phosphorylated eIF2α, through up-regulating the expression of ATF4, increases the expression of proteins important in amino acid metabolism and combating oxidative stress. PERK also promotes cell survival by phosphorylating and activating Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), which results in an increase in mRNAs encoding proteins important in maintaining redox homoeostasis. The activation of IRE1 and ATF6 leads to an increase in the expression of foldases, chaperones and proteins important in ERAD (ER-associated