TRAF family member-associated NF-κB activator (TANK) inhibits genotoxic nuclear factor κB activation by facilitating deubiquitinase USP10-dependent deubiquitination of TRAF6 ligase

Wei Wang, Xuan Huang, Hong Bo Xin, Mingui Fu, Aimin Xue, Zhaohui Wu

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

DNA damage-induced NF-κB activation plays a critical role in regulating cellular response to genotoxic stress. However, the molecular mechanisms controlling the magnitude and duration of this genotoxic NF-κB signaling cascade are poorly understood. We recently demonstrated that genotoxic NF-κB activation is regulated by reversible ubiquitination of several essential mediators involved in this signaling pathway. Here we show that TRAF family member-associated NF-κB activator (TANK) negatively regulates NF-κB activation by DNA damage via inhibiting ubiquitination of TRAF6. Despite the lack of a deubiquitination enzyme domain, TANK has been shown to negatively regulate the ubiquitination of TRAF proteins. We found TANK formed a complex with MCPIP1 (also known as ZC3H12A) and a deubiquitinase, USP10, which was essential for the USP10-dependent deubiquitination of TRAF6 and the resolution of genotoxic NF-κB activation upon DNA damage. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated deletion of TANK in human cells significantly enhanced NF-κB activation by genotoxic treatment, resulting in enhanced cell survival and increased inflammatory cytokine production. Furthermore, we found that the TANK-MCPIP1-USP10 complex also decreased TRAF6 ubiquitination in cells treated with IL-1β or LPS. In accordance, depletion of USP10 enhanced NF-κB activation induced by IL-1β or LPS. Collectively, our data demonstrate that TANK serves as an important negative regulator of NF-κB signaling cascades induced by genotoxic stress and IL-1R/Toll-like receptor stimulation in a manner dependent on MCPIP1/USP10-mediated TRAF6 deubiquitination.

Original languageEnglish (US)
Pages (from-to)13372-13385
Number of pages14
JournalJournal of Biological Chemistry
Volume290
Issue number21
DOIs
StatePublished - May 22 2015

Fingerprint

TNF Receptor-Associated Factor 6
Ligases
DNA Damage
Ubiquitination
Chemical activation
Interleukin-1
Clustered Regularly Interspaced Short Palindromic Repeats
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
DNA
Cells
Toll-Like Receptors
Cell Survival
Deubiquitinating Enzymes
Cytokines
Enzymes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

TRAF family member-associated NF-κB activator (TANK) inhibits genotoxic nuclear factor κB activation by facilitating deubiquitinase USP10-dependent deubiquitination of TRAF6 ligase. / Wang, Wei; Huang, Xuan; Xin, Hong Bo; Fu, Mingui; Xue, Aimin; Wu, Zhaohui.

In: Journal of Biological Chemistry, Vol. 290, No. 21, 22.05.2015, p. 13372-13385.

Research output: Contribution to journalArticle

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