P52rIPK Regulates the Molecular Cochaperone P58IPK To Mediate Control of the RNA-Dependent Protein Kinase in Response to Cytoplasmic Stress

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Abstract
The 52 kDa protein referred to as P52rIPK was first identified as a regulator of P58IPK, a cellular inhibitor of the RNA-dependent protein kinase (PKR). P52rIPK and P58IPK each possess structural domains implicated in stress signaling, including the charged domain of P52rIPK and the tetratricopeptide repeat (TPR) and DnaJ domains of P58IPK. The P52rIPK charged domain exhibits homology to the charged domains of Hsp90, including the Hsp90 geldanamycin-binding domain. Here we present an in-depth analysis of P52rIPK function and expression, which first revealed that the 114 amino acid charged domain was necessary and sufficient for interaction with P58IPK. This domain bound specifically to P58IPK TPR domain 7, the domain adjacent to the TPR motif required for P58IPK interaction with PKR, thus providing a mechanism for P52rIPK inhibition of P58IPK function. Both the charged domain of P52rIPK and the TPR 7 domain of P58IPK were required for P52rIPK to mediate downstream control of PKR activity, eIF2α phosphorylation, and cell growth. Furthermore, we found that P52rIPK and P58IPK formed a stable intracellular complex during the acute response to cytoplasmic stress induced by a variety of stimuli. We propose a model in which the P52rIPK charged domain functions as a TPR-specific signaling motif to directly regulate P58IPK within a larger cytoplasmic stress signaling cascade culminating in the control of PKR activity and cellular mRNA translation.

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