title: Methionine sulfoxide reductase B3 deficiency stimulates heme oxygenase-1 expression via ROS-dependent and Nrf2 activation pathways.
abstract: Methionine sulfoxide reductase B3 (MsrB3), which is primarily found in the endoplasmic reticulum (ER), is an important protein repair enzyme that stereospecifically reduces methionine-R-sulfoxide residues. We previously found that MsrB3 deficiency arrests the cell cycle at the G1/S stage through up-regulation of p21 and p27. In this study, we report a critical role of MsrB3 in gene expression of heme oxygenase-1 (HO-1), which has an anti-proliferative effect associated with p21 up-regulation. Depletion of MsrB3 elevated HO-1 expression in mammalian cells, whereas MsrB3 overexpression had no effect. MsrB3 deficiency increased cellular reactive oxygen species (ROS), particularly in the mitochondria. ER stress, which is associated with up-regulation of HO-1, was also induced by depletion of MsrB3. Treatment with N-acetylcysteine as an ROS scavenger reduced augmented HO-1 levels in MsrB3-depleted cells. MsrB3 deficiency activated Nrf2 transcription factor by enhancing its expression and nuclear import. The activation of Nrf2 induced by MsrB3 depletion was confirmed by increased expression levels of its other target genes, such as γ-glutamylcysteine ligase. Taken together, these data suggest that MsrB3 attenuates HO-1 induction by inhibiting ROS production, ER stress, and Nrf2 activation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea.
authors.forename: Geun-Hee
authors.initials: GH
authors.lastname: Kwak
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu, Republic of Korea. Electronic address: hykim@ynu.ac.kr.
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D051150:Methionine Sulfoxide Reductases / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D051150:Methionine Sulfoxide Reductases; C524352:MSRB3 protein, human; D000111:Acetylcysteine
keywords: Cell growth; ER stress; Heme oxygenease-1; Methionine sulfoxide reductase; MsrB3; Nrf2 activation