Ultraviolet light inhibits translation through activation of the unfolded protein response kinase PERK in the lumen of the endoplasmic reticulum

Shiyong Wu, Yuanyuan Hu, Ju Lin Wang, Madhumita Chatterjee, Yuguang Shi, Randal J. Kaufman

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Exposure to ultraviolet light can cause inflammation, premature skin aging, and cancer. UV irradiation alters the expression of multiple genes that encode functions to repair DNA damage, arrest cell growth, and induce apoptosis. In addition, UV irradiation inhibits protein synthesis, although the mechanism is not known. In this report, we show that UV irradiation induces phosphorylation of eukaryotic translation initiation factor 2 on the α-subunit (eIF2α) and inhibits protein synthesis in a dosage- and time-dependent manner. The UV-induced phosphorylation of eIF2α was prevented by the overexpression of a non-phosphorylatable mutant of eIF2α (S51A). PERK is an eIF2α protein kinase localized to the endoplasmic reticulum that is activated by the accumulation of unfolded proteins in the endoplasmic reticulum. Expression of trans-dominant-negative mutants of PERK also prevented eIF2α phosphorylation upon UV treatment and protected from the associated translation attenuation. The luminal domain of dominant-negative mutant PERK formed heterodimers with endogenous PERK to inhibit the PERK signaling pathway. In contrast, eIF2α phosphorylation was not inhibited by overexpression of a trans-dominant-negative mutant kinase, PKR, supporting the theory that UV-induced eIF2α phosphorylation is specifically mediated by PERK. These results support a novel mechanism by which UV irradiation regulates translation via an endoplasmic reticulum-stress signaling pathway.

Original languageEnglish (US)
Pages (from-to)18077-18083
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number20
DOIs
StatePublished - May 17 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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