Figure 2.

Beneficial and harmful effects of PERK activation. Normal PERK function is required for proinsulin folding, ER calcium balance, translation regulation, and cell survival, but PERK activation can also lead to cell death and loss of maturation markers. Activated by ER stress, low glucose, and low ER calcium, PERK phosphorylates eIF2α to simultaneously suppress global translation but selectively activate translation of some transcripts such as Atf4 and Aatf. Beneficial effects of PERK activation include suppression of translation when the ER is overloaded with peptide inputs, promotion of cell survival through activation of ATF4 and AATF, improved SERCA pump function by dephosphorylation of CLNX to derepress calcium transport, and proliferation. Harmful effects of PERK activation include suppression of translation of required genes including maturation factors and insulin itself (although PERK deletion also caused loss of MAFA and PDX1), as well as increased cell death through CHOP and inflammatory pathways. Green arrows indicate transcriptional regulation. AATF, apoptosis antagonizing transcription factor; AKT1, protein kinase B; ATF4, activating transcription factor 4; CALN, calcineurin; CHOP, C/EBP homologous protein; CLNX, calnexin; eIF2α, eukaryotic translation initiation factor 2 subunit 1; GRP78, glucose-regulated protein 78; Iapp, islet amyloid polypeptide precursor; IFNAR1, interferon α and β subunit 1; Ins1/2, insulin 1/2; MAFA, Maf bZIP transcription factor A; circled P indicates phosphorylation; PDX1, pancreatic and duodenal homeobox 1; PERK, protein kinase R-like ER kinase; UTR, untranslated region.