TRAF6 gene

The TRAF6 gene (TRAF6 stands for "TNF Receptor Associated Factor 6") is a protein-coding gene located on chromosome 11p12. The protein encoded by this gene belongs to the family of TNF receptor-associated factors (TRAF proteins).

TRAF proteins are associated with members of the TNF receptor superfamily and mediate their signal transduction. The TRAF-6 protein has an amino-terminal RING domain followed by four zinc finger motifs, a central coiled-coil region, and a highly conserved carboxyl-terminal domain known as the TRAF-C domain, which mediates signaling from members of the TNF receptor superfamily as well as the Toll/IL-1 family.

Signals from receptors such as CD40, TNFSF11/RANCE and interleukin-1 have been shown to be mediated by this protein (Cao Z et al. 1996). The encoded protein also interacts with various protein kinases, including IRAK1/IRAK, SRC and PKCzeta, establishing a link between different signaling pathways. TRAF6 protein as a signal transducer in the NF-kappaB signaling pathway, which activates IkappaB kinase (IKK) in response to proinflammatory cytokines (Shembade N et al. 2007). Its interaction with UBE2N/UBC13 and UBE2V1/UEV1A, which are ubiquitin-conjugating enzymes that catalyze the formation of polyubiquitin chains, has been shown to be required for IKK activation. The TRAF6 protein also interacts with the transforming growth factor (TGF) beta receptor complex and is required for Smad-independent activation of JNK and p38 kinases. It is a key molecule in antiviral innate and antigen-specific immune responses.

The encoded protein acts as an adaptor protein that appears to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (Ye H et al. 2002). Regulates osteoclast differentiation by mediating the activation of adaptor protein complex 1 (AP-1) and NF-kappa-B in response to stimulation by RANK-L.

Diseases associated with TRAF6 include:

• Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant (OMIN:
• and
• osteopetrosis.

1. Cao Z et al. (1996) TRAF6 is a signal transducer for interleukin-1. Nature 383:443-446
2. Shembade N et al. (2007) Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling. EMBO J 26:3910-3922.
3. Ye H et al. (2002) Distinct molecular mechanism for initiating TRAF6 signaling. Nature 418:443-447.