* 607043
TRAF3-INTERACTING PROTEIN 2; TRAF3IP2
Alternative titles; symbols
CHROMOSOME 6 OPEN READING FRAME 5; C6ORF5
NUCLEAR FACTOR KAPPA-B ACTIVATOR 1; ACT1
CONNECTION TO I-KAPPA-B KINASE AND STRESS-ACTIVATED PROTEIN KINASE; CIKS
CHROMOSOME 6 OPEN READING FRAME 4; C6ORF4
CHROMOSOME 6 OPEN READING FRAME 6; C6ORF6
HGNC Approved Gene Symbol: TRAF3IP2
Cytogenetic location: 6q21 Genomic coordinates (GRCh38) : 6:111,555,381-111,605,878 (from NCBI)
Gene-Phenotype Relationships
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q21 | ?Candidiasis, familial, 8 | 615527 | Autosomal recessive | 3 |
| {Psoriasis susceptibility 13} | 614070 | 3 |
TEXT
Cloning and Expression
Using mouse Nemo/Ikk-gamma (IKBKG; 300248) as bait in a yeast 2-hybrid screen, Leonardi et al. (2000) cloned CIKS from a human liver cDNA library. The deduced 574-amino acid protein contains a C-terminal leucine zipper. Northern blot analysis of multiple human tissues indicated ubiquitous expression of a 2.5-kb transcript.
Li et al. (2000) cloned a cDNA encoding ACT1 from a cDNA library constructed from embryonic kidney cells induced to display constitutive activation of nuclear factor kappa-B (NFKB; see 164011). The deduced 574-amino acid protein has a calculated molecular mass of 60 kD and contains a helix-loop-helix domain and a C-terminal coiled-coil domain. The helix-loop-helix domain shares 35% identity with the helix-loop-helix domain of upstream stimulatory factor-1 (USF1; 191523). Northern blot analysis detected highest expression in thymus, kidney, and placenta, moderate expression in heart, skeletal muscle, colon, liver, lung, and small intestine, and low expression in brain, spleen, and peripheral blood leukocytes.
By screening thymus, skeletal muscle, and fetal liver cDNA libraries, Morelli et al. (2000) identified 3 isoforms of ACT1 that they designated C6ORF4, C6ORF5, and C6ORF6. C6ORF4 encodes a deduced 575-amino acid protein. C6ORF5 and C6ORF6 result from the skipping of exon 2 and are differentiated by use of alternate polyadenylation signals, yielding identical proteins of 566 amino acids. Northern blot analysis detected 5.0- and 2.5-kb transcripts in all tissues examined, with a weak 3.8-kb transcript in heart, skeletal muscle, and pancreas.
Gene Function
Leonardi et al. (2000) verified the interaction between CIKS and IKK-gamma by in vitro binding assays using recombinant proteins and by coimmunoprecipitation of lysates of transfected HeLa cells or untransfected Jurkat T-leukemic cells. IKK-alpha (CHUK; 600664) and IKK-beta (IKBKB; 603258) also coimmunoprecipitated with CIKS. Using truncation mutants, the authors localized the binding domain to the N terminus of CIKS. HeLa cells transfected with increasing amounts of CIKS showed dose-dependent activation of an Ig kappa-B luciferase reporter plasmid, and the activation could be blocked by cotransfection with IKK-gamma. Cotransfection of CIKS with kinase-deficient mutants of NIK (MAP3K14; 604655), MEKK1 (MAP3K1: 600982), IKK-alpha, and IKK-beta indicated that CIKS activates NFKB exclusively through an IKK-dependent mechanism. Overexpressed CIKS also potently activated SAPK/JNK (MAPK8; 601158). Analysis of the binding activity of truncation mutants showed that the C terminus of CIK is involved in SAPK/JNK activation, whereas the N terminus is necessary and sufficient for kappa-B reporter activation.
Using gel shift assays, Li et al. (2000) confirmed constitutive activation of NFKB with transfection of ACT1 into human embryonic kidney cells. They also found constitutive activation of JNK and IKK. Disruption of the N-terminal helix-loop-helix domain of ACT1 completely abolished the interaction between ACT1 and the IKK complex as well as the activation of NFKB.
By mutation analysis, Pacifico et al. (2003) identified a sequence in the 5-prime flanking region of human CIKS that was essential for basal promoter activity in a canine kidney cell line. RT-PCR, Northern, and Western blot analyses showed that various proinflammatory cytokines upregulated CIKS expression in HeLa cells.
Using immunoprecipitation analysis, Qian et al. (2007) found that IL17 (603149) induced association of ACT1 with IL17RA (605461) in various cell types. The ACT1-IL17RA interaction required the SEFIR domain of IL17RA. Expression of Il17-dependent inflammation-related genes was abolished in Act1-deficient mouse cells. Mice lacking Act1 had delayed onset and lower severity of experimental allergic encephalomyelitis, as well as limited colitis. Qian et al. (2007) concluded that ACT1 is essential for IL17-dependent signaling in autoimmune and inflammatory disease.
Gene Structure
Morelli et al. (2000) determined that the ACT1 gene contains 10 exons and spans more than 50 kb. They also identified C6UAS, which overlaps exon 2 and is transcribed in the antisense orientation from the complementary strand of C6ORF4. C6UAS has no apparent open reading frame, but Morelli et al. (2000) provided experimental evidence that it has a regulatory function and can behave as an antisense RNA in the control of C6ORF4 translation.
Pacifico et al. (2003) mapped the CIKS transcription start site and found that the 5-prime flanking region was TATA-less, but it had initiator, GC, and CAAT boxes.
Biochemical Features
Zhang et al. (2013) reported the structure of the IL17RB SEFIR (for 'similar expression to FGFR and IL17R;' see 136350) domain at 1.8-angstrom resolution. SEFIR displays a 5-stranded parallel beta-sheet that is wrapped by 6 helices. Site-directed mutagenesis analysis identified helix alphaC as being critical for interaction with ACT1 and IL17E (IL25; 605658) signaling. This helix is also critical for ACT1 function and is conserved in IL17RA (605461) and IL17RC (610925). Helix alphaB, on the other hand, is important for ACT1 homodimerization, suggesting that distinct motifs participate in binding with different ligands. Zhang et al. (2013) proposed that the structure helps to explain IL17R intracellular signaling and the mechanism for the specificity of SEFIR versus the TIR (see TLR2, 603028) domain in their respective signaling pathways.
Mapping
Morelli et al. (2000) identified ACT1 within an EST clone that maps to chromosome 6q21.
Molecular Genetics
Psoriasis Susceptibility 13
Ellinghaus et al. (2010) and Huffmeier et al. (2010) independently identified association of a coding single-nucleotide polymorphism (SNP), rs33980500 (607043.0001), in the TRAF3IP2 gene with psoriasis susceptibility (PSORS13; 614070).
Familial Candidiasis 8
In an affected brother and sister from a consanguineous Algerian family with chronic mucocutaneous candidiasis (CANDF8; 615527), Boisson et al. (2013) identified homozygosity for a missense mutation in the TRAF3IP2 gene (T536I; 607043.0002). Neither patient displayed psoriasis.
Animal Model
Matsushima et al. (2010) identified spontaneous mutant mice with high levels of serum IgE and atopic dermatitis (AD; see 603165) in a colony of the KOR inbred strain that was derived from wild Japanese mice. Segregation analysis attributed the mutation to a single recessive locus, which the authors designated 'atopic dermatitis from Japanese mice' (adjm). Linkage and sequence analysis revealed that adjm mice carry a point mutation in the Traf3ip2 gene that leads to a gln214-to-ter (Q214X) substitution. Matsushima et al. (2010) proposed that the Traf3ip2 mutation causes hyper-IgE-emia through the Cd40 (TNFRSF5; 109535)- and B-cell activating factor (BAFF, or TNFSF13B; 603969)-mediated pathway in B cells and causes skin inflammation through the Il17-mediated pathway.
ALLELIC VARIANTS 2 Selected Examples):
.0001 PSORIASIS 13, SUSCEPTIBILITY TO
SNP: rs33980500, gnomAD: rs33980500, ClinVar: RCV000023605, RCV000455845, RCV001514434, RCV001824574
In a case-control genomewide association study of psoriasis susceptibility (PSORS13; 614070), Ellinghaus et al. (2010) identified a coding SNP, rs33980500, in exon 2 of the TRAF3IP2 gene. A C-to-T transition results in substitution of asn for asp at codon 19 (D19N). This SNP was significantly associated with risk for psoriasis vulgaris (P = 1.24 x 10(-16)) and psoriatic arthritis (P = 4.57 x 10(-12)).
In an independent case-control genomewide association study, Huffmeier et al. (2010) found significant association of rs33980500 with psoriatic arthritis in a subset of cases and controls (P = 1.13 x 10(-20), OR = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6 (602355), suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a novel and shared pathway for psoriatic arthritis and psoriasis vulgaris. Huffmeier et al. (2010) referred to the amino acid change correlated with this SNP as ASP10ASN.
Sonder et al. (2012) reconstituted mouse embryonic fibroblasts (MEFs) from Ciks-deficient mice with wildtype Ciks or with Ciks lacking the Traf6-binding site to explore the association between the human CIKs D10N mutant defective in TRAF6 binding and psoriasis susceptibility. They found that Ciks lacking the Traf6-binding site significantly impaired Il17 (see IL17A; 603149)-induced expression of target genes, but had no effect on the response to Il17 plus Tnf (TNFA; 191160). Tnf signals compensated Il17 signaling defects imposed by the Ciks mutant even for genes that were not induced by Tnf alone, including Ikbz (NFKBIZ; 608004), Cebpb (189965), and Cebpd (116898), which helped to regulate secondary gene expression in response to Il17. Experiments with mouse primary keratinocytes and primary dermal fibroblasts reproduced the findings in MEFs. Sonder et al. (2012) proposed that the CIKS mutant defective in TRAF6 binding may interfere with homeostatic maintenance of epithelial barriers and allow initiation of inflammatory responses, but that it retains the ability to mediate IL17-specific responses in the presence of TNF.
Using fibroblasts from a healthy individual who was homozygous for the D10N variant in TRAF3IP2, Boisson et al. (2013) observed a weak response to stimulation with IL17A and low but detectable GRO-alpha (155730) and IL6 (147620) induction. In addition, costimulation with IL17A and TNFA was synergistic in this individual's cells. Boisson et al. (2013) concluded that D10N is a hypomorphic, but not null, allele for cellular responses to IL17A, alone or in combination with TNFA.
.0002 CANDIDIASIS, FAMILIAL, 8 (1 family)
SNP: rs397518485, ClinVar: RCV000074416
In an affected brother and sister from a consanguineous Algerian family with chronic mucocutaneous candidiasis (CANDF8; 615527), Boisson et al. (2013) identified homozygosity for a c.1607C-T transition in the TRAF3IP2 gene, resulting in a thr536-to-ile (T536I) substitution at a highly conserved residue in the C-terminal part of the SEFIR domain. The mutation, which segregated with disease in the family, was not found in more than 10,000 chromosomes or in the 1000 Genomes Project or dbSNP (build 135) databases. Neither of the affected sibs displayed psoriasis. Functional analysis using patient fibroblasts and EBV-B cells demonstrated that the T536I mutant abolishes homotypic interactions with the SEFIR domain of IL17RA (605461), IL17RB (605458), and IL17RC (610925), but does not affect homodimerization or SEFIR-independent ACT1 interactions with other proteins. Patient fibroblasts did not produce IL6 (147620) in response to IL17A (603149) or IL17F (606496). Stimulation of patient peripheral blood mononuclear cells with IL2 (147680) and/or IL17E (605658) resulted in production of IL5 (147850) only in response to IL2, and there was no synergistic response to costimulation. Flow cytometric analysis indicated that the patients had higher proportions of IL17- and IL22 (605330)-producing cells but normal levels of IFNG (147570)-producing cells, suggesting that responsiveness to IL17 rather than production of the cytokine is critical for protection from chronic mucocutaneous candidiasis.
REFERENCES
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Boisson, B., Wang, C., Pedergnana, V., Wu, L., Cypowyj, S., Rybojad, M., Belkadi, A., Picard, C., Abel, L., Fieschi, C., Puel, A., Li, X., Casanova, J.-L. An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity 39: 676-686, 2013. [PubMed: 24120361] [Full Text: https://doi.org/10.1016/j.immuni.2013.09.002]
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Ellinghaus, E., Ellinghaus, D., Stuart, P. E., Nair, R. P., Debrus, S., Raelson, J. V., Belouchi, M., Fournier, H., Reinhard, C., Ding, J., Li, Y., Tejasvi, T., and 21 others. Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nature Genet. 42: 991-995, 2010. [PubMed: 20953188] [Full Text: https://doi.org/10.1038/ng.689]
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Huffmeier, U., Uebe, S., Ekici, A. B., Bowes, J., Giardina, E., Korendowych, E., Juneblad, K., Apel, M., McManus, R., Ho, P., Bruce, I. N., Ryan, A. W., and 18 others. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nature Genet. 42: 996-999, 2010. [PubMed: 20953186] [Full Text: https://doi.org/10.1038/ng.688]
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Leonardi, A., Chariot, A., Claudio, E., Cunningham, K., Siebenlist, U. CIKS, a connection to I-kappa-B kinase and stress-activated protein kinase. Proc. Nat. Acad. Sci. 97: 10494-10499, 2000. [PubMed: 10962033] [Full Text: https://doi.org/10.1073/pnas.190245697]
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Li, X., Commane, M., Nie, H., Hua, X., Chatterjee-Kishore, M., Wald, D., Haag, M., Stark, G. R. Act1, an NF-kappa-B-activating protein. Proc. Nat. Acad. Sci. 97: 10489-10493, 2000. [PubMed: 10962024] [Full Text: https://doi.org/10.1073/pnas.160265197]
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Matsushima, Y., Kikkawa, Y., Takada, T., Matsuoka, K., Seki, Y., Yoshida, H., Minegishi, Y., Karasuyama, H., Yonekawa, H. An atopic dermatitis-like skin disease with hyper-IgE-emia develops in mice carrying a spontaneous recessive point mutation in the Traf3ip2 (Act1/CIKS) gene. J. Immun. 185: 2340-2349, 2010. [PubMed: 20660351] [Full Text: https://doi.org/10.4049/jimmunol.0900694]
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Morelli, C., Magnanini, C., Mungall, A. J., Negrini, M., Barbanti-Brodano, G. Cloning and characterization of two overlapping genes in a subregion at 6q21 involved in replicative senescence and schizophrenia. Gene 252: 217-225, 2000. [PubMed: 10903453] [Full Text: https://doi.org/10.1016/s0378-1119(00)00231-6]
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Pacifico, F., Barone, C., Mellone, S., Di Jeso, B., Consiglio, E., Formisano, S., Vito, P., Leonardi, A. Promoter identification of CIKS, a novel NF-kappa-B activating gene, and regulation of its expression. Gene 307: 99-109, 2003. [PubMed: 12706892] [Full Text: https://doi.org/10.1016/s0378-1119(03)00448-7]
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Qian, Y., Liu, C., Hartupee, J., Altuntas, C. Z., Gulen, M. F., Jane-wit, D., Xiao, J., Lu, Y., Giltiay, N., Liu, J., Kordula, T., Zhang, Q.-W., Vallance, B., Swaidani, S., Aronica, M., Tuohy, V. K., Hamilton, T., Li, X. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nature Immun. 8: 247-256, 2007. [PubMed: 17277779] [Full Text: https://doi.org/10.1038/ni1439]
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Sonder, S. U., Paun, A., Ha, H.-L., Johnson, P. F., Siebenlist, U. CIKS/Act1-mediated signaling by IL-17 cytokines in context: implications for how a CIKS gene variant may predispose to psoriasis. J. Immun. 188: 5906-5914, 2012. [PubMed: 22581863] [Full Text: https://doi.org/10.4049/jimmunol.1103233]
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Zhang, B., Liu, C., Qian, W., Han, Y., Li, X., Deng, J. Crystal structure of IL-17 receptor B SEFIR domain. J. Immun. 190: 2320-2326, 2013. Note: Erratum: J. Immun. 190: 4910 only, 2013. [PubMed: 23355738] [Full Text: https://doi.org/10.4049/jimmunol.1202922]
Paul J. Converse - updated : 2/26/2015
Marla J. F. O'Neill - updated : 11/14/2013
Ada Hamosh - updated : 6/24/2011
Paul J. Converse - updated : 11/12/2007
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