Article

I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction.

Tularik, Inc., South San Francisco, CA 94080, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/1996; 93(16):8241-6. DOI: 10.1073/pnas.93.16.8241
Source: PubMed

ABSTRACT Tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins associate with and transduce signals from TNF receptor 2, CD40, and presumably other members of the TNF receptor superfamily. TRAF2 is required for CD40- and TNF-mediated activation of the transcription factor NF-kappa B. Here we describe the isolation and characterization of a novel TRAF-interacting protein, I-TRAF, that binds to the conserved TRAF-C domain of the three known TRAFs. Overexpression of I-TRAF inhibits TRAF2-mediated NF-kappa B activation signaled by CD40 and both TNF receptors. Thus, I-TRAF appears as a natural regulator of TRAF function that may act by maintaining TRAFs in a latent state.

Full-text

Available from: Dave Goeddel, Jun 03, 2015
0 Followers
 · 
102 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The signaling pathway downstream of TNF receptor (TNFR) is involved in the induction of a wide range of cellular processes, including cell proliferation, activation, differentiation and apoptosis. TNFR-associated factor 2 (TRAF2) is a key adaptor molecule in TNFR signaling complexes that promotes downstream signaling cascades, such as nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase activation. TRAF-interacting protein (TRIP) is a known cellular binding partner of TRAF2 and inhibits TNF-induced NF-κB activation. Recent findings that TRIP plays a multifunctional role in antiviral response, cell proliferation, apoptosis and embryonic development have increased our interest in exploring how TRIP can affect the TNFR-signaling pathway on a molecular level. In our current study, we demonstrated that TRIP is negatively involved in the TNF-induced inflammatory response through the downregulation of proinflammatory cytokine production. Here, we demonstrated that the TRAF2-TRIP interaction inhibits K63-linked TRAF2 ubiquitination by inhibiting TRAF2 E3 ubiquitin (Ub) ligase activity. The TRAF2-TRIP interaction inhibited the binding of sphingosine-1-phosphate (S1P), which is a cofactor of TRAF2 E3 Ub ligase, to the TRAF2 RING domain. Finally, we demonstrated that TRIP functions as a negative regulator of proinflammatory cytokine production by inhibiting TNF-induced NF-κB activation. These results indicate that TRIP is an important cellular regulator of the TNF-induced inflammatory response. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 02/2015; 290(15). DOI:10.1074/jbc.M114.609685 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    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 lack of a deubiquitination enzyme domain, TANK was shown to negatively regulate ubiquitination of TRAF proteins. We found TANK formed a complex with MCPIP1 (also known as ZC3H12A) and a deubiquitinase USP10, which was essential for USP10-dependent deubiquitination of TRAF6 and resolution of genotoxic NF-κB activation upon DNA damage. CRISPR/Cas9-mediated deletion of TANK in human cells significantly enhanced NF-κB activation by genotoxic treatments, resulting in enhanced cell survival and increased inflammatory cytokine production upon genotoxic drug treatment. Furthermore, we found that 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/TLR stimulation in a manner dependent on MCPIP1/USP10-mediated TRAF6 deubiquitination. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 04/2015; DOI:10.1074/jbc.M115.643767 · 4.60 Impact Factor