Format

Send to

Choose Destination
J Biol Chem. 2015 May 22;290(21):13372-85. doi: 10.1074/jbc.M115.643767. Epub 2015 Apr 10.

TRAF Family Member-associated NF-κB Activator (TANK) Inhibits Genotoxic Nuclear Factor κB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination of TRAF6 Ligase.

Author information

1
From the Department of Pathology and Laboratory Medicine and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
2
the Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
3
the Department of Basic Medical Science, University of Missouri Kansas City, Kansas City, Missouri 64108, and.
4
the Department of Forensic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China.
5
From the Department of Pathology and Laboratory Medicine and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163, zwu6@uthsc.edu.

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.

KEYWORDS:

DNA damage; NF-κB; TANK; TNF receptor-associated factor (TRAF); ubiquitin-dependent protease; ubiquitylation (ubiquitination)

PMID:
25861989
PMCID:
PMC4505586
DOI:
10.1074/jbc.M115.643767
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center