| First Author | Roobol A | Year | 2015 |
| Journal | Biochem J | Volume | 465 |
| Issue | 2 | Pages | 213-25 |
| PubMed ID | 25329545 | Mgi Jnum | J:218404 |
| Mgi Id | MGI:5617428 | Doi | 10.1042/BJ20140852 |
| Citation | Roobol A, et al. (2015) p58IPK is an inhibitor of the eIF2alpha kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity. Biochem J 465(2):213-25 |
| abstractText | One of the key cellular responses to stress is the attenuation of mRNA translation and protein synthesis via the phosphorylation of eIF2alpha (eukaryotic translation initiation factor 2alpha). This is mediated by four eIF2alpha kinases and it has been suggested that each kinase is specific to the cellular stress imposed. In the present study, we show that both PERK (PKR-like endoplasmic reticulum kinase/eIF2alpha kinase 3) and GCN2 (general control non-derepressible 2/eIF2alpha kinase 4) are required for the stress responses associated with conditions encountered by cells overexpressing secreted recombinant protein. Importantly, whereas GCN2 is the kinase that is activated following cold-shock/hypothermic culturing of mammalian cells, PERK and GCN2 have overlapping functions since knockdown of one of these at the mRNA level is compensated for by the cell by up-regulating levels of the other. The protein p58IPK {also known as DnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2alpha kinases PKR (dsRNA-dependent protein kinase/eIF2alpha kinase 2) and PERK and hence prevent or delay eIF2alpha phosphorylation and consequent inhibition of translation. However, we show that p58IPK is a general inhibitor of the eIF2alpha kinases in that it also interacts with GCN2. Thus forced overexpression of cytoplasmic p58 delays eIF2alpha phosphorylation, suppresses GCN2 phosphorylation and prolongs protein synthesis under endoplasmic reticulum (ER), hypothermic and prolonged culture stress conditions. Taken together, our data suggest that there is considerable cross talk between the eIF2alpha kinases to ensure that protein synthesis is tightly regulated. Their activation is controlled by p58 and the expression levels and localization of this protein are crucial in the capacity the cells to respond to cellular stress via control of protein synthesis rates and subsequent folding in the ER. |
