Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 21, Pages 13372-13385Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.643767
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Funding
- NCI/National Institutes of Health [R01CA149251]
- American Cancer Society [RSG-13-186-01-CSM]
- National Institute of Health [R21AI103618]
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DNA damage-induced NF-kappa B 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-kappa B signaling cascade are poorly understood. We recently demonstrated that genotoxic NF-kappa B activation is regulated by reversible ubiquitination of several essential mediators involved in this signaling pathway. Here we show that TRAF family member-associated NF-kappa B activator (TANK) negatively regulates NF-kappa B 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-kappa B activation upon DNA damage. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated deletion of TANK in human cells significantly enhanced NF-kappa B 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-1 beta or LPS. In accordance, depletion of USP10 enhanced NF-kappa B activation induced by IL-1 beta or LPS. Collectively, our data demonstrate that TANK serves as an important negative regulator of NF-kappa B signaling cascades induced by genotoxic stress and IL-1R/Toll-like receptor stimulation in a manner dependent on MCPIP1/USP10-mediated TRAF6 deubiquitination.
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