title: TRAF Family Member-associated NF-κB Activator (TANK) Inhibits Genotoxic Nuclear Factor κB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination of TRAF6 Ligase.
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.
authors: From the Department of Pathology and Laboratory Medicine and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors: Wei
authors: W
authors: Wang
authors: the Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors: Xuan
authors: X
authors: Huang
authors: the Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors: Hong-Bo
authors: HB
authors: Xin
authors: the Department of Basic Medical Science, University of Missouri Kansas City, Kansas City, Missouri 64108, and.
authors: Mingui
authors: M
authors: Fu
authors: the Department of Forensic Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors: Aimin
authors: A
authors: Xue
authors: 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.
authors: Zhao-Hui
authors: ZH
authors: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000502:physiology; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; C484406:TANK protein, human; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; C431363:USP10 protein, human; D025801:Ubiquitin; D012260:Ribonucleases; C541320:Zc3h12a protein, mouse; D043222:Ubiquitin Thiolesterase
keywords: DNA damage; NF-κB; TANK; TNF receptor-associated factor (TRAF); ubiquitin-dependent protease; ubiquitylation (ubiquitination)