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Phosphorylation-Dependent Lys⁶³-Linked Polyubiquitination of Daxx Is Essential for Sustained TNF-–Induced ASK1 Activation

¹ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri; ² Department of Oral Pathology, Hokkaido University, Sapporo, Japan; ³ Department of Parasitology, Kurume University Medical School, Kurume, Japan; and ⁴ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Nobuo Horikoshi, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-728, Boston, MA 02215. Phone: 617-735-3308; Fax: 617-735-3327; E-Mail: nhorikos{at}bidmc.harvard.edu.

Key Words: ASK1 • Daxx • polyubiquitination

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 Lys⁶³ (K63)-linked polyubiquitination on Lys¹²² 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- (TNF-)–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- signaling pathway. [Cancer Res 2009;69(19):7512–7]

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