title: Ultraviolet light inhibits translation through activation of the unfolded protein response kinase PERK in the lumen of the endoplasmic reticulum.
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 alpha-subunit (eIF2alpha) and inhibits protein synthesis in a dosage- and time-dependent manner. The UV-induced phosphorylation of eIF2alpha was prevented by the overexpression of a non-phosphorylatable mutant of eIF2alpha (S51A). PERK is an eIF2alpha 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 eIF2alpha 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, eIF2alpha phosphorylation was not inhibited by overexpression of a trans-dominant-negative mutant kinase, PKR, supporting the theory that UV-induced eIF2alpha 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.
authors.affiliation: Department of Radiation Oncology and Biological Chemistry, The Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA. shiyongw@umich.edu
authors.forename: Shiyong
authors.initials: S
authors.lastname: Wu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Hu
authors.forename: Ju-Lin
authors.initials: JL
authors.lastname: Wang
authors.forename: Madhumita
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Shi
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D019556:COS Cells; D006224:Cricetinae; D019281:Dimerization; D004307:Dose-Response Relationship, Radiation; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000528:radiation effects*; D004789:Enzyme Activation / Q000528:radiation effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000528:radiation effects*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays / Q000009:adverse effects*; D019892:eIF-2 Kinase / Q000378:metabolism / Q000528:radiation effects*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D019892:eIF-2 Kinase