p58(IPK) is an Inhibitor of the eIF2{alpha} Kinase GCN2 and its Localisation and Expression Underpin Protein Synthesis and ER Processing Capacity

One of the key cellular responses to stress is the attenuation of mRNA translation and protein synthesis via the phosphorylation of eIF2α. This is mediated by four eIF2α kinases and it has been suggested that each kinase is specific to the cellular stress imposed. Herein we show that both PERK and GCN2 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 p58(IPK) is known to inhibit the eIF2α kinases PKR and PERK and hence prevent or delay eIF2α phosphorylation and consequent inhibition of translation. However, we show that p58(IPK) is a general inhibitor of the eIF2α kinases in that it also interacts with GCN2. Thus forced over-expression of cytoplasmic p58 delays eIF2α phosphorylation, suppresses GCN2 phosphorylation and prolongs protein synthesis under ER, hypothermic and prolonged culture stress conditions. Taken together our data suggest that there is considerable cross-talk between the eIF2α kinases to ensure that protein synthesis is tightly regulated. Their activation is controlled by p58 and the expression levels and localisation of this protein are cruci...

Source: BJ Cell - October 20, 2014 Category: Biochemistry Authors: A Roobol, J Roobol, A Bastide, J RP Knight, A E Willis, C Mark Smales Tags: BJ Gene Source Type: research