Phosphorylation-dependent Lys63-linked polyubiquitination of Daxx is essential for sustained TNF-{alpha}-induced ASK1 activation.
Apoptosis signal-regulating kinase 1 (ASK1) is a key regulatory kinase in the proapoptotic response to various stresses. ASK1 phosphorylation of Daxx, an ASK1 activator protein, increases Daxx accumulation in cells and further enhances ASK1 activity through a positive feedback mechanism. Here, we show that ASK1-dependent phosphorylation of Daxx induces Lys(63) (K63)-linked polyubiquitination on Lys(122) of Daxx. Polyubiquitination is dispensable for Daxx accumulation or Daxx interaction with ASK1 because mutant Daxx deficient in polyubiquitin still exhibits ASK1-dependent accumulation and interaction with cellular ASK1. However, K63-linked Daxx polyubiquitination is required for tumor necrosis factor-alpha (TNF-alpha)-induced activation of ASK1. Therefore, K63-linked polyubiquitination of Daxx functions as a molecular switch to initiate and amplify the stress kinase response in the TNF-alpha signaling pathway.
Fukuyo
Yayoi
Y
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
Kitamura
Tetsuya
T
Inoue
Masahiro
M
Horikoshi
Nobuko T
NT
Higashikubo
Ryuji
R
Hunt
Clayton R
CR
Usheva
Anny
A
Horikoshi
Nobuo
N
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D025821:Polyubiquitin / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D014409:Tumor Necrosis Factor-alpha; D025821:Polyubiquitin; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D008239:Lysine