HGNC Approved Gene Symbol: TRAF6
Cytogenetic location: 11p12 Genomic coordinates (GRCh38): 11:36,483,769-36,510,272 (from NCBI)
TRAF6 is a signal transducer in the NF-kappa-B (see 164011) pathway that activates I-kappa-B kinase (IKK; see 600664) in response to proinflammatory cytokines (summary by Deng et al., 2000).
The transcription factor NF-kappa-B is activated by many cytokines that signal through different cell surface receptors. Members of the TRAF protein family have been implicated in the activation of this transcription factor by the tumor necrosis factor (TNF; 191160) superfamily. By database analysis and screening human cDNA libraries, Cao et al. (1996) cloned TRAF6, a novel human TRAF. The deduced 522-amino acid protein has a calculated molecular mass of 57 kD. It has a cysteine-rich N terminus that includes a RING finger and 5 potential zinc fingers, followed by a TRAF-N domain and a C-terminal TRAF-C domain. Northern blot analysis detected variable expression of TRAF6 transcripts of about 2.5, 4, and 8 kb in all human tissues examined.
Cao et al. (1996) showed that when overexpressed in cultured human cells, TRAF6 activates NF-kappa-B. A dominant-negative mutant of TRAF6 inhibited this activation signaled by interleukin-1 (IL1A; 147760). IL1A treatment of the same cells induced the association of TRAF6 with interleukin-1-associated kinase (IRAK; 300283), a serine/threonine kinase that is rapidly recruited to the IL1A receptor after IL1A induction. The findings were interpreted as indicating that TRAF proteins function as signal transducers for distinct receptor families in that TRAF6 participates in IL1A signaling.
TRANCE (or RANKL; 602642), a TNF family member, and its receptor, RANK (603499), are critical regulators of dendritic cell and osteoclast function. Wong et al. (1999) demonstrated that TRANCE activates the antiapoptotic serine/threonine kinase PKB (AKT1; 164730) through a signaling complex involving SRC (190090) and TRAF6. A deficiency in SRC or addition of SRC family kinase inhibitors blocked TRANCE-mediated PKB activation in osteoclasts. SRC and TRAF6 interacted with each other and with RANK upon receptor engagement. TRAF6, in turn, enhanced the kinase activity of SRC, leading to tyrosine phosphorylation of downstream signaling molecules such as CBL (165360). These results defined a mechanism by which TRANCE activates SRC family kinases and PKB, and provided evidence of cross-talk between TRAF proteins and SRC family kinases.
Deng et al. (2000) purified a heterodimeric protein complex that links TRAF6 to IKK activation. Peptide mass fingerprinting analysis revealed that this complex, which they called TRIKA1 (TRAF6-regulated IKK activator-1), is composed of the ubiquitin conjugating enzyme UBC13 (603679) and the UBC-like protein UBE2V1 (602995). They found that TRAF6, a RING domain protein, functions together with UBC13/UBE2V1 to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin. Blockade of this polyubiquitin chain synthesis, but not inhibition of the proteasome, prevents the activation of IKK by TRAF6. These results unveil a new regulatory function for ubiquitin, in which IKK is activated through the assembly of K63-linked polyubiquitin chains.
Wang et al. (2001) determined that TRIKA2, the second factor required for IKK activation in the presence of TRAF6 and TRIKA1, is composed of TAK1 (602614) and its binding partners, TAB1 (602615) and TAB2 (605101).
Takayanagi et al. (2000) demonstrated that T-cell production of interferon-gamma (IFNG; 147570) strongly suppresses osteoclastogenesis by interfering with the RANKL-RANK signaling pathway. IFNG induces rapid degradation of the RANK adaptor protein, TRAF6, resulting in strong inhibition of the RANKL-induced activation of the transcription factor NFKB and JNK (601158). This inhibition of osteoclastogenesis could be rescued by overexpressing TRAF6 in precursor cells, indicating that TRAF6 is the target critical for the IFNG action. Furthermore, Takayanagi et al. (2000) provided evidence that the accelerated degradation of TRAF6 requires both its ubiquitination, which is initiated by RANKL, and IFNG-induced activation of the ubiquitin-proteasome system. Takayanagi et al. (2000) concluded that their study showed that there is crosstalk between the tumor necrosis factor and IFN families of cytokines, through which IFNG provides a negative link between T-cell activation and bone resorption.
Takatsuna et al. (2003) found that mouse Tifa (609028) bound Traf6 directly, and they presented evidence that TIFA is involved in TRAF6 activation of NFKB and JNK. Ea et al. (2004) showed that human TIFA induced the oligomerization and polyubiquitination of TRAF6, leading to activation of TAK1 and IKK.
Using a yeast 2-hybrid assay, Wooff et al. (2004) found that mouse Traf6 interacted with human UBC13, but not with human MMS2 (UBE2V2; 603001) or UEV1A (UBE2V1). Mutation analysis revealed that the N-terminal RING finger and zinc finger domains of Traf6 were necessary and sufficient for the interaction. These domains also mediated Traf6 self-association.
Akiyama et al. (2005) demonstrated that deficiency in TRAF6 results in disorganized distribution of medullary thymic epithelial cells (TECs) and the absence of mature medullary TECs. Engraftment of thymic stroma of Traf6-null embryos into athymic nude mice induced autoimmunity. Thus, Akiyama et al. (2005) concluded that TRAF6 directs the development of thymic stroma and represents a critical point of regulation for self-tolerance and autoimmunity.
Bai et al. (2005) found that Fhl2 (602633) inhibited association of Traf6 with Rank in mouse osteoclast precursors. Consequently, Fhl2 reduced Traf6-induced NF-kappa-B activity and Rank signaling, delaying Rankl-induced osteoclastogenesis.
Bai et al. (2008) found that Traf6 interacted with the transcription factor Runx1 (151385) in mouse osteoclast nuclei. Fhl2 increased the nuclear abundance of Traf6 in transfected cells and interacted with nuclear Traf6 and Runx1. Fhl2 did not interact with Runx1 in the absence of Traf6. The Traf6-Runx1-Fhl2 complex bound Runx1 recognition sequences in the Fhl2 promoter and induced Fhl2 expression. Traf6 also reduced Fhl2 content via polyubiquitination of Fhl2, followed by Fhl2 proteasomal degradation.
To dissect biochemically Toll-like receptor signaling, Hacker et al. (2006) established a system for isolating signaling complexes assembled by dimerized adaptors. Using MyD88 (602170) as a prototypic adaptor, they identified TRAF3 (601896) as a new component of Toll/interleukin-1 receptor signaling complexes that is recruited along with TRAF6. Using myeloid cells from Traf3- and Traf6-deficient mice, Hacker et al. (2006) demonstrated that TRAF3 is essential for the induction of type I interferons and the antiinflammatory cytokine interleukin-10 (IL10; 124092), but is dispensable for expression of proinflammatory cytokines. In fact, Traf3-deficient cells overproduced proinflammatory cytokines owing to defective IL10 production. Despite their structural similarity, the functions of TRAF3 and TRAF6 are largely distinct. TRAF3 is also recruited to the adaptor TRIF (607601) and is required for marshalling the protein kinase TBK1 (604834) into Toll/interleukin-1 receptor signaling complexes, thereby explaining its unique role in activation of the interferon response.
Pearce et al. (2009) demonstrated that TRAF6 regulates CD8 (see 186910) memory T cell development after infection by modulating fatty acid metabolism. They showed that mice with a T cell-specific deletion of TRAF6 mounted robust CD8 antigen-specific effector T cell responses, but had a profound defect in their ability to generate memory T cells that was characterized by the disappearance of antigen-specific cells in the weeks after primary immunization. Microarray analysis revealed that TRAF6-deficient CD8 T cells exhibited altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lacking TRAF6 displayed defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the antidiabetic drug metformin restored FAO and CD8 memory T cell generation in the absence of TRAF6. This treatment also increased CD8 memory T cells in wildtype mice, and consequently was able to considerably improve the efficacy of an experimental anticancer vaccine.
Yang et al. (2009) found that the protein kinase Akt (164730) undergoes lysine-63 chain ubiquitination, which is important for Akt membrane localization and phosphorylation. TRAF6 was found to be a direct E3 ligase for Akt and was essential for Akt ubiquitination, membrane recruitment, and phosphorylation upon growth factor stimulation. The human cancer-associated Akt mutant (164730.0001) displayed an increase in Akt ubiquitination, in turn contributing to the enhancement of Akt membrane localization and phosphorylation. Thus, Yang et al. (2009) concluded that Akt ubiquitination is an important step for oncogenic Akt activation.
Xia et al. (2009) found that unanchored polyubiquitin chains synthesized by TRAF6 and UBCH5C (602963) activate the IKK (see 600664) complex. Disassembly of the polyubiquitin chains by deubiquitination enzymes prevented TAK1 (602614) and IKK activation. Xia et al. (2009) concluded that unanchored polyubiquitin chains directly activate TAK1 and IKK, suggesting a new mechanism of protein kinase regulation.
Shembade et al. (2010) showed that A20 (191163) inhibits the E3 ligase activities of TRAF6, TRAF2 (601895), and cIAP1 (601712) by antagonizing interactions with E2 ubiquitin-conjugating enzymes UBC13 (603679) and UBCH5C. A20, together with the regulatory molecule TAX1BP1 (605326), interacted with UBC13 and UBCH5C and triggered their ubiquitination and proteasome-dependent degradation. These findings suggested a mechanism of A20 action in the inhibition of inflammatory signaling pathways.
Zucchelli et al. (2010) identified TRAF6 as a common player in both inherited and sporadic cases of Parkinson disease (PD; see 168600). TRAF6 bound misfolded mutant DJ1 (PARK7; 602533) and SNCA (163890), and both proteins were found to be substrates of TRAF6 ligase activity in vivo. Rather than conventional lys63 (K63) assembly, TRAF6 promoted atypical ubiquitin linkage formation to both PD targets that shared K6-, K27- and K29- mediated ubiquitination. TRAF6 stimulated the accumulation of insoluble and polyubiquitinated mutant DJ1 into cytoplasmic aggregates. In human postmortem brains of PD patients, TRAF6 protein colocalized with SNCA in Lewy bodies. The authors proposed a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.
West et al. (2011) demonstrated that engagement of a subset of Toll-like receptors (TLR1, 601194; TLR2, 603028; and TLR4, 603030) results in the recruitment of mitochondria to macrophage phagosomes and augments mitochondrial reactive oxygen species (mROS) production. This response involves translocation of a TLR signaling adaptor, TRAF6, to mitochondria, where it engages the protein ECSIT (608388), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase (115500) in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. West et al. (2011) concluded that their results revealed a novel pathway linking innate immune signaling to mitochondria, implicated mROS as an important component of antibacterial responses, and further established mitochondria as hubs for innate immune signaling.
By proteomic analysis of lipopolysaccharide (LPS)-stimulated mouse embryonic fibroblasts, Dauphinee et al. (2013) identified Sash1 (607955) as part of the Tlr4 signaling pathway. Knockdown of SASH1 in human microvascular endothelial cells decreased NFKB luciferase activity in response to LPS, but not in response to TLR2, TLR3 (603029), TLR5 (603031), or other TRAF6-dependent receptors. SASH1 knockdown also resulted in decreased production of IL6 (147620) and IL10, but it did not affect interferon-regulated genes. Coimmunoprecipitation analysis showed that residues 852 to 860 of SASH1 bound to the C-terminal region of TRAF6 containing the coiled-coil domain and that the interaction depended on LPS. SASH1 did not interact with MYD88, IRAKs, or other TRAF molecules. Overexpression of SASH1, in the absence of stimulation, induced autoubiquitination of TRAF6 without direct interaction of SASH1 with ubiquitin-conjugating enzymes, such as UBC13. Further coimmunoprecipitation experiments showed that the large SASH1 molecule acted as a scaffold by binding TAK1 and the IKK complex molecules IKBKA (CHUK; 600664) and IKBKB (603258) to facilitate signaling to NFKB. SASH1 also regulated TAK1 ubiquitination and activation of the downstream MAPKs JNK1 and p38 (MAPK14; 600289). Knockdown of SASH1 significantly reduced endothelial cell migration in response to LPS. Dauphinee et al. (2013) concluded that SASH1 is a novel regulator of TLR4 signaling through its formation of a molecular complex around TRAF6.
Using transfected HEK293T cells, Chen et al. (2015) showed that overexpression of RNF166 (617178) enhanced activation of the IFNB (147640) promoter after infection with Sendai RNA virus (SeV). Knockdown of RNF166 in HEK293T cells inhibited IFNB promoter activation, IFNB transcription, and IFNB secretion in response to SeV infection. Similar results were observed with knockdown of RNF166 in HeLa cells. RNF166 interacted with TRAF3 and TRAF6, and knockdown of RNF166 suppressed SeV-induced ubiquitination of TRAF3 and TRAF6. Chen et al. (2015) proposed that RNF166 positively regulates RNA virus-triggered IFNB production by enhancing ubiquitination of TRAF3 and TRAF6.
Wang et al. (2020) reported that the host E3 ubiquitin ligase ANAPC2 (606946), a core subunit of the anaphase-promoting complex/cyclosome, interacts with the mycobacterial protein Rv0222 and promotes the attachment of lys11-linked ubiquitin chains to lys76 of Rv0222 in order to suppress the expression of proinflammatory cytokines. Inhibition of ANAPC2 by specific shRNA abolished the inhibitory effect of Rv0222 on proinflammatory responses. Moreover, mutation of the ubiquitination site on Rv0222 impaired the inhibition of proinflammatory cytokines by Rv0222 and reduced virulence during infection in mice. Mechanistically, lys11-linked ubiquitination of Rv0222 by ANAPC2 facilitates the recruitment of the protein tyrosine phosphatase SHP1 (PTPN6; 176883) to the adaptor protein TRAF6, preventing the lys63-linked ubiquitination and activation of TRAF6.
Ye et al. (2002) reported the crystal structures of TRAF6, alone and in complex with TRAF6-binding peptides from CD40 and TRANCER (RANK), members of the TNFR superfamily, to gain insight into the mechanism by which TRAF6 mediates several signaling cascades. A 40-degree difference in the directions of the bound peptides in TRAF6 and TRAF2 showed that there are marked structural differences between receptor recognition by TRAF6 and other TRAFs. The structural determinant of the peptide-TRAF6 interaction revealed a Pro-X-Glu-X-X-(aromatic/acidic residue) TRAF6-binding motif, which is present not only in CD40 and RANK but also in the 3 IRAK adaptor kinases for IL1R/Toll-like receptor signaling (see 604459). Cell-permeable peptides with the TRAF6-binding motif inhibited TRAF6 signaling, which indicated their potential as therapeutic modulators. Ye et al. (2002) concluded that their studies identified a universal mechanism by which TRAF6 regulates several signaling cascades in adaptive immunity, innate immunity, and bone homeostasis.
One of the E3 ligases responsible for K63-linked NEMO polyubiquitination is TRAF6, which participates in several signaling pathways controlling immunity, osteoclastogenesis, skin development, and brain function. Gautheron et al. (2010) determined that a site at the N terminus of NEMO (300248) binds the coiled-coil domain of TRAF6 and apparently works in concert with NEMO's ubiquitin-binding domain to provide a dual mode of TRAF6 recognition. The E57K NEMO mutation, found in a mild form of incontinentia pigmenti (308300), resulted in impaired TRAF6 binding and IL1-beta (147720) signaling. In contrast, activation of NF-kappa-B by TNF-alpha was not affected. The authors concluded that the NEMO-TRAF6 interaction has physiologic relevance.
Stumpf (2020) mapped the TRAF6 gene to chromosome 11p12 based on an alignment of the TRAF6 sequence (GenBank BC031052) with the genomic sequence (GRCh38).
In members of 2 Maltese pedigrees with osteoporosis mapping to chromosome 11q12 (BMND8; 611738), Vidal et al. (2007) sequenced the TRAF6 gene and identified 3 noncoding sequence variants, including a -721A-T transversion in the promoter region of the gene that was present in 3 affected members of 1 family. The promoter variant was also found in heterozygosity in 3 of 82 unrelated postmenopausal women and in 2 of 350 control chromosomes from the general population.
TRAFs are essential to perinatal and postnatal survival. Lomaga et al. (1999) reported that mice deficient in Traf6 exhibited osteopetrosis with defects in bone remodeling and tooth eruption due to impaired tartrate-resistant acid phosphatase (TRAP; see 171640)-positive osteoclast function. The authors noted that osteoclasts are absent in Opgl (602642)-deficient mice. In Traf6 knockout mice, however, osteoclasts were present but lacked contact with bone surfaces and were unable to resorb significant amounts of bone. Unlike other TRAFs, TRAF6 is required for IL1 signaling. IL1B (147720) stimulation failed to induce NFKB or JNK/SAPK activation in cells from Traf6 -/- mice. Inducible nitrous oxide synthase (INOS; see 163729) production in response to TNF plus IFNG, but not to IL1, was intact in Traf6-deficient mice. B lymphocytes from knockout mice exposed to anti-CD40 (see 109535) or LPS failed to proliferate or to activate NFKB. T-lymphocyte proliferation was unaffected by Traf6 deletion.
Naito et al. (2002) reported that Traf6 -/- mice had defective development of epidermal appendices, including guard hair follicles, sweat glands, sebaceous glands of back skin, and modified sebaceous glands, such as meibomian, anal, and preputial glands. Excluding the sebaceous gland impairment, these abnormal phenotypes are identical to those observed in 'Tabby' (Ta), 'downless' (dl), and 'crinkled' (cr) mice, which are models of hypohidrotic (anhidrotic) ectodermal dysplasia (224900) in humans resulting from mutations in the EDA1 (305100), EDAR (604095), and EDARADD (606603) genes, respectively. Beta-catenin (CTNNB1; 116806) and mucosal addressin cell adhesion molecule-1 (MADCAM1; 102670), an early marker of developing guard-hair follicles, were absent in the skin of Traf6-deficient embryos. Thus, TRAF6 is essential for development of epidermal appendices. Traf6 did not associate with the cytoplasmic tail of the dl protein, which, when mutated, results in hypohidrotic ectodermal dysplasia. However, Traf6 associated with XEDAR (300276) and TAJ (606122), which are EDAR-related members of the TNFR superfamily that are expressed at high levels in epidermal appendices. The results suggested that TRAF6 may transduce signals emanating from XEDAR or TAJ that are associated with development of epidermal appendices.
Ohazama et al. (2004) found that Traf6 mutant mice had abnormalities in molar teeth that were similar to but more severe than those produced by mutations in Eda signaling molecules. Sections of first mandibular molars revealed a major reduction in cusp shape and height compared with wildtype, demonstrating that Traf6 plays an essential role in cusp formation.
King et al. (2006) generated healthy mice lacking Traf6 specifically in T lymphocytes. At 10 to 12 weeks of age, these mice developed splenomegaly and lymphadenopathy, with increased B-cell and Cd4 (186940)-positive T-cell numbers, but fewer Cd8 (see 186910)-positive T cells. Histopathologic analysis showed systemic inflammation in multiple organs of mutant mice. Cd4-positive/Cd25 (IL2RA; 147730)-positive regulatory T cells were present and appeared functional in mutant mice, but proliferation of Traf6 -/- T cells could not be suppressed by wildtype or mutant regulatory T cells, suggesting the presence of a responder T-cell mechanism necessary to render T cells susceptible to regulation. The resistance to suppression was accompanied by hyperactivation of PI3K (see 601232)-dependent pathways. King et al. (2006) concluded that TRAF6 is important in maintaining the balance between immune activation and suppression.
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