TRAF6

Fig1. AngII-induced MAPK/TGF-β1/TRAF6/TAK1 signaling pathway in postoperative atrial fibrillation. (Daoliang Zhang, 2017)

What is TRAF6 Protein?

TRAF6 gene (TNF receptor associated factor 6) is a protein coding gene which situated on the short arm of chromosome 11 at locus 11p12. The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from, members of the TNF receptor superfamily. This protein has an amino terminal RING domain which is followed by four zinc-finger motifs, a central coiled-coil region and a highly conserved carboxyl terminal domain, known as the TRAF-C domain and mediates signaling from members of the TNF receptor superfamily as well as the Toll/IL-1 family. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The TRAF6 protein is consisted of 522 amino acids and TRAF6 molecular weight is approximately 59.6 kDa.

What is the Function of TRAF6 Protein?

TRAF6 protein (TNF receptor associated factor 6) is a key signal transduction molecule belonging to the tumor necrosis factor receptor associated factor family. It acts as an E3 ubiquitin ligase and acts as a signal converter in the cell. TRAF6 activates signaling pathways including NF-κB and MAPKs through its TRAF domain interaction with a variety of cell surface receptors to regulate immune response, inflammatory processes, and cell survival and apoptosis. In addition, TRAF6 promotes polyubiquitination of multiple proteins, including itself, by binding to the E2 ubiquitin binding enzyme Ubc13/Uev1A, activating downstream signaling pathways. This involves ubiquitination and phosphorylation of AKT, phosphorylation of TAK1, and cross-action through the JAK-STAT pathway.

TRAF6 Related Signaling Pathway

The autoubiquitination of TRAF6 is independent of its ability to activate the NF-κB and MAPK pathways. After RANKL binds to RANK, TRAF6 triggers the NF-κB signaling pathway, leading to nuclear transfer of NF-κB and transcription of target genes through activation of IKKs. After TLRs activation, MyD88 attracts IRAK-4 to TLRs, which is subsequently activated by IRAK-1 phosphorylation and interacts with TRAF6 to activate the IKK complex, leading to the activation of MAP kinase (JNK, p38 MAPK) and NF-κB. The JAK2/STAT3 signaling pathway is closely related to RANKL expression. After IL-6 binds to IL-6R, JAK kinase is activated, STAT3 is phosphorylated, and RANKL gene transcription is activated, thus a large amount of RANKL is expressed.

TRAF6 Related Diseases

Abnormal activity of TRAF6 protein has been associated with a variety of diseases, especially in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, where TRAF6 is involved in inflammatory responses and immune cell regulation through activation of NF-κB and MAPK signaling pathways; In tumor development, TRAF6 is closely related to the occurrence and development of some cancers by promoting the proliferation, survival and metastasis of tumor cells. In addition, TRAF6 also plays a role in bone metabolism, and its dysfunction may lead to bone diseases such as osteoporosis. Therefore, TRAF6 is a target with potential therapeutic value in a variety of pathological processes.

Bioapplications of TRAF6

TRAF6 has become a hot target for drug development due to its central role in a variety of inflammatory and immune-related diseases. Currently, off-the-shelf applications for TRAF6 are focused on developing small molecule inhibitors or biologics to regulate its activity to treat autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and certain types of cancer. For example, several studies have identified compounds that block TRAF6 and its interacting partners, which inhibit the activation of NF-κB and MAPK signaling pathways, reducing inflammation and tumor cell proliferation. Although no drugs specifically targeting TRAF6 are currently widely available in the clinic, advances in research in this area offer hope for new strategies to treat these diseases in the future.

Case Study 1: Han Xu, 2023

Ample evidence reveals that glycolysis is crucial to tumor progression; however, the underlying mechanism of its drug resistance is still worth being further explored. TRAF6, an E3 ubiquitin ligase, is well recognized to overexpress in various types of cancer, which predicts a poor prognosis. In this study, TRAF6 was expressed more significantly in the case of triple-negative breast cancer (TNBC) than in other of breast cancers, promoting chemoresistance to paclitaxel; that inhibited TRAF6 expression in the chemoresistant TNBC (TNBC-CR) cells enhanced the sensitivity by decreasing glucose uptake and lactate production; that TRAF6 regulated glycolysis and facilitated chemoresistance via binding directly to PKM2; and that overexpressing PKM2 in the TNBC-CR cells with TRAF6 knocked down regained significantly TRAF6-dependent drug resistance and glycolysis. Additionally, TRAF6 could facilitate PKM2-mediated glycolysis and chemoresistance in animal models and clinical tumor tissues.

Fig1. Western blotting conducted to detect the expression of TRAF6 in TNBC parental and chemoresistant cells.

Fig2. Binding proteins of TRAF6 identified by immunoprecipitation and silver nitrate staining.

Case Study 2: Anubrita Das, 2023

For many inflammatory cytokines, the response elicited is dependent on the recruitment of the tumour necrosis factor receptor-associated factor (TRAF) family of adaptor proteins. All TRAF proteins have a trimeric C-terminal TRAF domain, while at the N-terminus most TRAFs have a RING domain that forms dimers. The symmetry mismatch of the N- and C-terminal halves of TRAF proteins means that when receptors cluster, it is presumed that RING dimers connect TRAF trimers to form a network. Here, using purified TRAF6 proteins, researchers provide direct evidence in support of this model, and show that TRAF6 trimers bind Lys63-linked ubiquitin chains to promote their processive assembly.

Fig3. Native PAGE gel showing oligomerisation of TRAF6 wild-type and dimer interface mutant (F118A) RZCC proteins.

Fig4. The addition of ubiquitin to di- and hepta-ubiquitin substrates at each time point is shown for both TRAF6 RZ3 and RZCC.

TRAF6 has several biochemical functions, for example, histone deacetylase binding,identical protein binding,ligase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by TRAF6 itself. We selected most functions TRAF6 had, and list some proteins which have the same functions with TRAF6. You can find most of the proteins on our site.

TRAF6 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with TRAF6 here. Most of them are supplied by our site. Hope this information will be useful for your research of TRAF6.

TRAF2;TAX1BP1;TRAF5