P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling.
The unfolded protein response, which is activated in response to the loss of endoplasmic reticulum (ER) Ca(2+) 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 2alpha (eIF2alpha)-like ER kinase/activation transcription factor (ATF) 4 pathway. Modulation of P58(IPK) levels altered the phosphorylation status of eIF2alpha, and thereby affected expression of its downstream targets, ATF4 and Gadd153. Overexpression of P58(IPK) inhibited eIF2alpha phosphorylation and reduced ATF4 and Gadd153 protein accumulation, whereas silencing of P58(IPK) expression enhanced pancreatic eIF2alpha-like ER kinase and eIF2alpha 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 eIF2alpha signaling, and thus attenuate the unfolded protein response.
van Huizen
Rika
R
Laboratory of Cellular and Molecular Biology, National Institute on Aging/NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. HuizenRi@grc.nia.nih.gov
Martindale
Jennifer L
JL
Gorospe
Myriam
M
Holbrook
Nikki J
NJ
D051702:Activating Transcription Factor 6; D017209:Apoptosis; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology*; D020868:Gene Silencing; D050956:HSP40 Heat-Shock Proteins; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D017510:Protein Folding; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D050956:HSP40 Heat-Shock Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C497249:DDIT3 protein, human; C494651:DNAJC3 protein, human