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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
Published on: November 2, 2018
Phosphorylation-dependent Lys63-linked polyubiquitination of Daxx is essential for sustained TNF-{alpha}-induced ASK1
Yayoi Fukuyo1, Tetsuya Kitamura, Masahiro Inoue
1Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
Abstract:
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.
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