P58IPK, a Novel Endoplasmic Reticulum Stress-inducible Protein and Potential Negative Regulator of eIF2α Signaling

• Published in: The Journal of biological chemistry Vol. 278; no. 18; pp. 15558 - 15564
• Main Authors: van Huizen, Rika, Martindale, Jennifer L., Gorospe, Myriam, Holbrook, Nikki J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 02.05.2003
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M212074200

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 P58IPK, an inhibitor of the interferon-induced double-stranded RNA-activated protein kinase, as induced during ER stress. Additional studies suggested that p58IPK induction was mediated via ATF6 and that P58IPK played a role in down-regulating the activity of the pancreatic eIF2 kinase/eukaryotic initiation factor 2α (eIF2α)-like ER kinase/activation transcription factor (ATF) 4 pathway. Modulation of P58IPK levels altered the phosphorylation status of eIF2α, and thereby affected expression of its downstream targets, ATF4 and Gadd153. Overexpression of P58IPK inhibited eIF2α phosphorylation and reduced ATF4 and Gadd153 protein accumulation, whereas silencing of P58IPK expression enhanced pancreatic eIF2α-like ER kinase and eIF2α phosphorylation and increased ATF4 and Gadd153 accumulation. These findings implicate P58IPK as an important component of a negative feedback loop used by the cell to inhibit eIF2α signaling, and thus attenuate the unfolded protein response.