Mammalian ECD protein is a novel negative regulator of the PERK arm of the unfolded protein response

Appolinaire A. Olou, Aniruddha Sarkar, Aditya Bele, Channabasavaiah B Gurumurthy, Riyaz A. Mir, Shalis A. Ammons, Sameer Mirza, Irfana Saleem, Fumihiko Urano, Hamid Band, Vimla Band

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Mammalian Ecdysoneless (ECD) is a highly conserved ortholog of the Drosophila Ecd gene product whose mutations impair the synthesis of Ecdysone and produce cell-autonomous survival defects, but the mechanisms by which ECD functions are largely unknown. Here we present evidence that ECD regulates the endoplasmic reticulum (ER) stress response. ER stress induction led to a reduced ECD protein level, but this effect was not seen in PKR-like ER kinase knockout (PERK-KO) or phosphodeficient eukaryotic translation initiation factor 2α (eIF2α) mouse embryonic fibroblasts (MEFs); moreover, ECD mRNA levels were increased, suggesting impaired ECD translation as the mechanism for reduced protein levels. ECD colocalizes and coimmunoprecipitates with PERK and GRP78. ECD depletion increased the levels of both phospho-PERK (p-PERK) and p-eIF2α, and these effects were enhanced upon ER stress induction. Reciprocally, overexpression of ECD led to marked decreases in p-PERK, p-eIF2α, and ATF4 levels but robust increases in GRP78 protein levels. However, GRP78 mRNA levels were unchanged, suggesting a posttranscriptional event. Knockdown of GRP78 reversed the attenuating effect of ECD overexpression on PERK signaling. Significantly, overexpression of ECD provided a survival advantage to cells upon ER stress induction. Taken together, our data demonstrate that ECD promotes survival upon ER stress by increasing GRP78 protein levels to enhance the adaptive folding protein in the ER to attenuate PERK signaling.

Original languageEnglish (US)
Article numbere00030-17
JournalMolecular and cellular biology
Volume37
Issue number18
DOIs
StatePublished - Sep 1 2017

Keywords

  • Cell survival
  • ECD
  • ER
  • GRP78
  • PERK
  • UPR

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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