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J. Biol. Chem., Vol. 278, Issue 18, 15558-15564, May 2, 2003

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P58^IPK, a Novel Endoplasmic Reticulum Stress-inducible Protein and Potential Negative Regulator of eIF2 Signaling^*

Rika van Huizen^§, Jennifer L. Martindale, Myriam Gorospe, and Nikki J. Holbrook^¶

From the  Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, Maryland 21224 and the ^¶ Section of Geriatrics, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520

The unfolded protein response, which is activated in response to the loss of endoplasmic reticulum (ER) Ca²⁺ homeostasis and/or the accumulation of misfolded, unassembled, or aggregated proteins in the ER lumen, involves both transcriptional and translational regulation. In the current studies we sought to identify novel ER stress-induced genes by conducting microarray analysis on tunicamycin-treated cells. We identified P58^IPK, an inhibitor of the interferon-induced double-stranded RNA-activated protein kinase, as induced during ER stress. Additional studies suggested that p58^IPK induction was mediated via ATF6 and that P58^IPK played a role in down-regulating the activity of the pancreatic eIF2 kinase/eukaryotic initiation factor 2 (eIF2)-like ER kinase/activation transcription factor (ATF) 4 pathway. Modulation of P58^IPK levels altered the phosphorylation status of eIF2, and thereby affected expression of its downstream targets, ATF4 and Gadd153. Overexpression of P58^IPK inhibited eIF2 phosphorylation and reduced ATF4 and Gadd153 protein accumulation, whereas silencing of P58^IPK expression enhanced pancreatic eIF2-like ER kinase and eIF2 phosphorylation and increased ATF4 and Gadd153 accumulation. These findings implicate P58^IPK as an important component of a negative feedback loop used by the cell to inhibit eIF2 signaling, and thus attenuate the unfolded protein response.

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