title: Thioredoxin-1 functions as a molecular switch regulating the oxidative stress-induced activation of MST1.
abstract: The mammalian STE20-like kinase-1 (MST1), a multifunctional serine-threonine kinase in mammalian cells, has been recently implicated in the mediation of oxidative stress-induced signaling processes that lead to cell death. However, the molecular mechanism by which oxidative stress induces the stimulation of MST1 remains unclear. In this study, we found that thioredoxin-1 was physically associated with MST1 in intact cells and that this interaction was abolished by H2O2. Thioredoxin-1, by binding to the SARAH domain of MST1, inhibited the homodimerization and autophosphorylation of MST1, thereby preventing its activation. Furthermore, TNF-α prevented the physical interaction between thioredoxin-1 and MST1 and promoted the homodimerization and activation of MST1. The effect of TNF-α on MST1 activation was reversed by the reducing agent N-acetyl-l-cysteine. Taken together, our results suggest that thioredoxin-1 functions as a molecular switch to turn off the oxidative stress-induced activation of MST1.
authors.affiliation: Laboratory of Cell Death and Human Diseases, School of Life Sciences, South Korea.
authors.forename: Ji Soo
authors.initials: JS
authors.lastname: Chae
authors.affiliation: Laboratory of Cell Death and Human Diseases, School of Life Sciences, South Korea.
authors.forename: Sang
authors.initials: S
authors.lastname: Gil Hwang
authors.affiliation: Department of Biological Sciences, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.affiliation: Laboratory of Cell Death and Human Diseases, School of Life Sciences, South Korea; School of Pharmacy, Korea University, Seoul 136-701, South Korea. Electronic address: ejchoi@korea.ac.kr.
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000737:chemistry / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000099317:Hippo Kinases
chemical_list: D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D013879:Thioredoxins; D014409:Tumor Necrosis Factor-alpha; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases
keywords: Free radicals; MST1; Reactive oxygen species; TNF-α; Thioredoxin-1