Eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is an enzyme that in humans is encoded by the EIF2AK3 gene.
One key regulator of β-cell development or function is Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) (EIF2AK3). Although it is a ubiquitous protein, it is highly expressed in the pancreas and essential for normal development and function of the insulin-secreting β-cells. PERK is a type I ER transmembrane protein, which has a lumenal domain similar to the ER stress sensing domain of IRE1 and a cytosolic domain similar to the kinase domain of the known eIF2α kinases, PKR and HRI. An important function of PERK is to attenuate global protein synthesis through phosphorylation of eIF2α during the UPR. The eIF2α phosphorylation inhibits eIF2B, a GTP exchange factor, decreasing ternary complex formation and subsequently abrogating protein translation. Translational upregulation of ATF4 by PERK/eIF2α signaling transcriptionally activates the expression of downstream ER stress-inducible genes, such as GRP78, CHOP and Herp. Activation of PERK signaling also induces G0-G1 arrest of cells due to repression of cyclin D1 synthesis.
Soon after its discovery, PERK was found to be activated by endoplasmic reticulum (ER) stress. ER stress occurs when protein load exceeds ER protein-folding capacity. The ER stress response, also called unfolded protein response (UPR), is induced by ER stress as an adaptive mechanism to bring the folding capacity of ER and the unfolded/misfolded protein back to normal physiological state. Three stress sensors are activated and mediated the unfolded protein response: inositol-requiring 1 (IRE1), activating transcription factor 6 (ATF 6), and PERK. Both IRE1 and PERK are type I transmembrane proteins and share similar, homologous luminal domain. In the resting state, IRE1 and PERK exist as monomers and form a reversible but stable complex with ER chaperone protein BiP through the luminal domains. During ER stress, disruption of protein folding induces dissociation of BiP from PERK and IRE1, leading to oligomerization and activation of both proteins. Activation of PERK under ER stress leads to global translational attenuation and specific translational induction of ATF4 which further induce transcription of the Chop and Gadd34 genes, whereas IRE1 activation results in splicing of transcription factor XBP1 into active form, which in turn induces transcription of ER chaperones (such as BiP and ERp72) and ER-associated protein degradation genes (such as EDEM). ATF6 is a type II transmembrane protein that also binds with BiP causing its retention in the ER when it is inactive. In response to ER stress, BiP dissociates from ATF6, leading to translocation of ATF6 from ER to Golgi whereby it undergoes proteolytic cleavage. The cleaved cytosolic domain further undergoes translocation into the nucleus to enhance transcription of ER stress target genes such as BiP, ERp72 and Chop.
and Alzheimer's disease are pathologically characterized by the intracellular or extracellular accumulation of misfolded proteins or mutated gene products. Thus, occurrences of ER stress and UPR activation have been observed in the affected neuronal cells. Mounting evidence suggests that ER chaperones are highly induced by UPR activation to ameliorate the accumulation of misfolded proteins and protect neuronal cells against neurotoxicity. Impairment of the functions of the involved chaperones leads to failure of relieving ER stress and eventual apoptosis of neuronal cells. This is supported by the development of neurological disorders in knockout mouse models of ER chaperones and co-chaperones.S-nitrosylated protein disulfide isomerase (PDI) was found in the brain samples of Parkinson’s or Alzheimer’s patients and exposure of the cultured neurons to NMDA that induced Ca2+ influx and nitric oxide production also resulted in s-nitrosylation of PDI. PDI catalyzes thio-disulfide exchange facilitating the disulfide bond formation and rearrangement reaction. In response to ER stress, PDI is usually upregulated and protects neuronal cells from ischemic injury. S-nitrosylation of PDI inhibits its enzymatic activity and leads to the accumulation of polyubiquitinated proteins and activation of UPR. On the other hand, overexpression of wild-type PDI attenuates UPR and protects cells against apoptosis induced by ER stress inducers such as tunicamycin which inhibits N-linked protein glycosylation and thapsigargin which is an inhibitor of ER Ca2+-ATPase.
Reference:Min Ni. ROLE OF GRP78 AND ITS NOVEL CYTOSOLIC ISOFORM GRP78VAIN REGULATING THE UNFOLDED PROTEIN RESPONSE IN CANCER
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