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

Fukuyo, Yayoi; Kitamura, Tatsuya; Inoue, Masahiro; Horikoshi, Nobuko T.; Higashikubo, Ryuji; Hunt, Clayton R.; Usheva, Anny; Horikoshi, Nobuo

doi:10.1158/0008-5472.can-09-2148

Cited by 17 publications

(11 citation statements)

References 21 publications

(22 reference statements)

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“… 52 Finally, ASK1-mediated phosphorylation of DAXX at S176 and S184 regulates K63-linked polyubiquitylation of Lys122, a modification required for sustained activation of JNK. 53 …”

Section: Discussionmentioning

confidence: 99%

DNA damage-induced regulatory interplay between DAXX, p53, ATM kinase and Wip1 phosphatase

Bražina¹,

Švadlenka²,

Macůrek

et al. 2015

Cell Cycle

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Death domain-associated protein 6 (DAXX) is a histone chaperone, putative regulator of apoptosis and transcription, and candidate modulator of p53-mediated gene expression following DNA damage. DAXX becomes phosphorylated upon DNA damage, however regulation of this modification, and its relationship to p53 remain unclear. Here we show that in human cells exposed to ionizing radiation or genotoxic drugs etoposide and neocarzinostatin, DAXX became rapidly phosphorylated in an ATM kinase-dependent manner. Our deletion and site-directed mutagenesis experiments identified Serine 564 (S564) as the dominant ATM-targeted site of DAXX, and immunofluorescence experiments revealed localization of S564-phosphorylated DAXX to PML nuclear bodies. Furthermore, using a panel of human cell types, we identified the p53-regulated Wip1 protein phosphatase as a key negative regulator of DAXX phosphorylation at S564, both in vitro and in cells. Consistent with the emerging oncogenic role of Wip1, its DAXX-dephosphorylating impact was most apparent in cancer cell lines harboring gain-of-function mutant and/or overexpressed Wip1. Unexpectedly, while Wip1 depletion increased DAXX phosphorylation both before and after DNA damage and increased p53 stability and transcriptional activity, knock-down of DAXX impacted neither p53 stabilization nor p53-mediated expression of Gadd45a, Noxa, Mdm2, p21, Puma, Sesn2, Tigar or Wip1. Consistently, analyses of cells with genetic, TALEN-mediated DAXX deletion corroborated the notion that neither phosphorylated nor non-phosphorylated DAXX is required for p53-mediated gene expression upon DNA damage. Overall, we identify ATM kinase and Wip1 phosphatase as opposing regulators of DAXX-S564 phosphorylation, and propose that the role of DAXX phosphorylation and DAXX itself are independent of p53-mediated gene expression.

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“… 52 Finally, ASK1-mediated phosphorylation of DAXX at S176 and S184 regulates K63-linked polyubiquitylation of Lys122, a modification required for sustained activation of JNK. 53 …”

Section: Discussionmentioning

confidence: 99%

DNA damage-induced regulatory interplay between DAXX, p53, ATM kinase and Wip1 phosphatase

Bražina¹,

Švadlenka²,

Macůrek

et al. 2015

Cell Cycle

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“…45 Phosphorylation-dependent Daxx with K63linked ubiquitination functions as a molecular switch to initiate and amplify the stress kinase response in the TNFα signaling pathway. 46 Some members of TRAFs have been identified to act for K63-linked ubiquitination. 47,48 IKK is activated by TRAF6, involving K63-linked polyUb chains, but not for proteasomal degradation.…”

Section: Methodsmentioning

confidence: 99%

Viral oncoprotein LMP1 disrupts p53-induced cell cycle arrest and apoptosis through modulating K63-linked ubiquitination of p53

Xiao

et al. 2012

Cell Cycle

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Disruption of the gatekeeper p53 tumor suppressor is involved in various virus-associated tumorigeneses, with aberrant ubiquitination as the major cause of p53 abnormalities in virus-associated tumors. Of note, wild-type p53 is accumulated in Epstein-Barr virus (EBV)-associated tumors, especially in nasopharyngeal carcinoma (NPC). We have previously identified that p53 is accumulated and phosphorylated by EBV oncoprotein latent membrane protein 1 (LMP1) in NPC. Here, we further found that LMP1 promoted p53 accumulation via two distinct ubiquitin modifications. LMP1 promoted p53 stability and accumulation by suppressing K48-linked ubiquitination of p53 mediated by E3 ligase MDM2, which is associated with its phosphorylation at Ser20, while increasing the levels of total cellular ubiquitinated p53. LMP1 also induced K63-linked ubiquitination of p53 by interacting with tumor necrosis factor receptor-associated factor 2 (TRAF2), thus contributing to p53 accumulation. Furthermore, LMP1 rescued tumor cell apoptosis and cell cycle arrest mediated by K63-linked ubiquitination of p53. Collectively, these results demonstrate aberrant ubiquitin modifications of p53 and its biological functions by viral protein LMP1, which has broad implications to the pathogenesis of multiple EBV-associated tumors.

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“…DAXX is a pro-apoptotic protein associated with the death receptor FAS in the cytosol (4), and mediates apoptosis through the FAS-DAXX-ASK1-MAP2K axis to activate JNK and p38 mitogen-activated protein kinase (MAPK) cascades (5,89,90) (Figure 3A). A positive feedback loop between DAXX and ASK1 (apoptosis signal-regulating kinase 1) was observed, such that DAXX activates ASK1, which in turn phosphorylates DAXX (91) (Figure 3B). Cellular stress, such as glucose deprivation, activates the ASK1–MEK–MAPK signaling cascade via an association of DAXX and TRAF2 with ASK1 (92,93) (Figure 3B).…”

Section: Daxx-regulated Processesmentioning

confidence: 99%

DAXX in cancer: phenomena, processes, mechanisms and regulation

Mahmud

Liao

2019

Nucleic Acids Research

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DAXX displays complex biological functions. Remarkably, DAXX overexpression is a common feature in diverse cancers, which correlates with tumorigenesis, disease progression and treatment resistance. Structurally, DAXX is modular with an N-terminal helical bundle, a docking site for many DAXX interactors (e.g. p53 and ATRX). DAXX’s central region folds with the H3.3/H4 dimer, providing a H3.3-specific chaperoning function. DAXX has two functionally critical SUMO-interacting motifs. These modules are connected by disordered regions. DAXX’s structural features provide a framework for deciphering how DAXX mechanistically imparts its functions and how its activity is regulated. DAXX modulates transcription through binding to transcription factors, epigenetic modifiers, and chromatin remodelers. DAXX’s localization in the PML nuclear bodies also plays roles in transcriptional regulation. DAXX-regulated genes are likely important effectors of its biological functions. Deposition of H3.3 and its interactions with epigenetic modifiers are likely key events for DAXX to regulate transcription, DNA repair, and viral infection. Interactions between DAXX and its partners directly impact apoptosis and cell signaling. DAXX’s activity is regulated by posttranslational modifications and ubiquitin-dependent degradation. Notably, the tumor suppressor SPOP promotes DAXX degradation in phase-separated droplets. We summarize here our current understanding of DAXX’s complex functions with a focus on how it promotes oncogenesis.

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

Cited by 17 publications

References 21 publications

DNA damage-induced regulatory interplay between DAXX, p53, ATM kinase and Wip1 phosphatase

DNA damage-induced regulatory interplay between DAXX, p53, ATM kinase and Wip1 phosphatase

Viral oncoprotein LMP1 disrupts p53-induced cell cycle arrest and apoptosis through modulating K63-linked ubiquitination of p53

DAXX in cancer: phenomena, processes, mechanisms and regulation

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