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Family in Amphioxus, the Basal Chordate TNF Receptor-Associated Genomic and Functional Uniqueness of the TNF Receptor-Associated Factor Gene Family in Amphioxus, the Basal Chordate This information is current as Shaochun Yuan, Tong Liu, Shengfeng Huang, Tao Wu, Ling of September 26, 2021. Huang, Huiling Liu, Xin Tao, Manyi Yang, Kui Wu, Yanhong Yu, Meiling Dong and Anlong Xu J Immunol 2009; 183:4560-4568; Prepublished online 14 September 2009; doi: 10.4049/jimmunol.0901537 Downloaded from http://www.jimmunol.org/content/183/7/4560 Supplementary http://www.jimmunol.org/content/suppl/2009/09/14/jimmunol.090153 Material 7.DC1 http://www.jimmunol.org/ References This article cites 38 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/183/7/4560.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Genomic and Functional Uniqueness of the TNF Receptor-Associated Factor Gene Family in Amphioxus, the Basal Chordate1 Shaochun Yuan, Tong Liu, Shengfeng Huang, Tao Wu, Ling Huang, Huiling Liu, Xin Tao, Manyi Yang, Kui Wu, Yanhong Yu, Meiling Dong, and Anlong Xu2 The TNF-associated factor (TRAF) family, the crucial adaptor group in innate immune signaling, increased to 24 in amphioxus, the oldest lineage of the Chordata. To address how these expanded molecules evolved to adapt to the changing TRAF mediated signaling pathways, here we conducted genomic and functional comparisons of four distinct amphioxus TRAF groups with their human counterparts. We showed that lineage-specific duplication and rearrangement were responsible for the expansion of amphioxus TRAF1/2 and 3 lineages, whereas TRAF4 and 6 maintained a relatively stable genome and protein structure. Am- Downloaded from phioxus TRAF1/2 and 3 molecules displayed various expression patterns in response to microbial infection, and some of them can attenuate the NF-␬B activation mediated by human TRAF2 and 6. Amphioxus TRAF4 presented two unique functions: activation of the NF-␬B pathway and involvement in somite formation. Although amphioxus TRAF6 was conserved in activating NF-␬B pathway for antibacterial defense, the mechanism was not the same as that observed in humans. In summary, our findings reveal the evolutionary uniqueness of the TRAF family in this basal chordate, and suggest that genomic duplication and functional divergence of the TRAF family are important for the current form of the TRAF-mediated signaling pathways in humans. The http://www.jimmunol.org/ Journal of Immunology, 2009, 183: 4560–4568. umor necrosis factor receptor-associated factors (TRAFs)3 genitor cells (3). It also binds the ste20 kinase msn and specifically are crucial adaptors linking immune receptors and inter- activates the JNK apoptosis pathway when triggered by Eiger, a T mediate signal transducers to a variety of immune re- unique TNF homologue in Drosophila (4). However, human sponses and developmental processes. There are six TRAFs in TRAF4 is not associated with classical TNFRs but serves as a mammals, three in Drosophila, and one in Caenorhabditis elegans negative regulator of TRIF (Toll/IL-1R resistance domain contain- (1). The TRAF family can be classified into three major groups, ing adaptor-inducing IFN-␤)-dependent pathways in the vertebrate by guest on September 26, 2021 two ancestral groups, TRAF4 and TRAF6, and the newly evolved TLR system (5). Several studies also implicate its role in human group comprising TRAF1, 2, 3, and 5 (2). All TRAF proteins share diseases and carcinogenesis (6, 7). a similar structure but differ from one another mainly in physio- DTRAF2, the null mutant of which shows strong immune logical function. deficiencies and affects normal dorsal-ventral (D-V) patterning DTRAF1, the ortholog of human TRAF4, is predominantly ex- in Drosophila embryos, physically and functionally interacts pressed during nervous system development and in epithelial pro- with Pelle to mediate the Toll-MyD88-Dorsal pathway (8, 9). Humans TRAF6, the ortholog of DTRAF2, has not only con- served its ancestral role in TLR signal transduction but also State Key Laboratory of Biocontrol, National Engineering Research Center of South China Sea Marine Biotechnology, Department of Biochemistry, College of Life Sci- adapted to the increasingly complex TNF system, having di- ences, Sun Yat-sen (Zhongshan) University, Guangzhou, People’s Republic of China verse functions from immunity to development processes, such Received for publication May 15, 2009. Accepted for publication July 17, 2009. as the development of lymph nodes, skin, and the CNS (10). In The costs of publication of this article were defrayed in part by the payment of page addition, human TRAF6 can be recruited by the IL-1R subfam- charges. This article must therefore be hereby marked advertisement in accordance ily that binds specific IL-1-related cytokines through their ex- with 18 U.S.C. Section 1734 solely to indicate this fact. tracellular Ig-like structures to participate in multiple immuno- 1 This work was supported by Project 2007CB815800 of the National Basic Research Program (973), Projects 2006AA09Z433 and 2008AA092603 of the State High-Tech logical and inflammatory processes (11). Development Project (863), Project 2007DFA30840 of International S&T Coopera- Although knowledge of the functions of DTRAF3 remains tion Program from the Ministry of Science and Technology of China, a key project (0107) from the Ministry of Education, a key project of Commission of Science and elusive, those of TRAF1, 2, 3, and 5 are well documented in Technology of Guangdong Province and Guangzhou City, a project of Sun Yet-sen humans. Upon differing TNFR engagement, TRAF2 and 5 are University Science Foundation, and the First Degree Supporting Project 20080440119 involved in the activation of JNK and NF-␬B signaling (12, 13), of China Postdoctoral Science Foundation. 2 whereas TRAF3 functions as an inhibitor of TRAF2- or 5-me- Address correspondence and reprint requests to Dr. Anlong Xu, Department of ␬ Biochemistry, College of Life Sciences, Sun Yat-Sen (Zhongshan) University, 135 diated activation of the noncanonical NF- B pathway (14, 15). XinGangXi Road, 510275, Guangzhou, People’s Republic of China. E-mail address: In addition to the cooperation with classical TNFRs, new stud- [email protected]. ies highlight their crucial roles in the induction of type I IFN, 3 Abbreviations used in this paper: TRAF, TNF-associated factor; Amphi, refers to all the critical component of innate defense against viral infections. amphioxus species; Bbt, Branchiostoma belcheri tsingtauense; Bf, Branchiostoma floridae; BC, bacterially challenged; ORF, open reading frame; TIR, Toll/IL-1R re- For example, TRAF2 participates in the antiviral action of IFN sistance domain; TRIF, Toll/IL-1R resistance domain containing adaptor-inducing by rapidly binding to the IFNAR1 subunit (16). TRAF3 directly IFN-␤; UC, unchallenged. and specifically interacts with several components of antiviral Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 pathways, such as TRIF, TBK1, and Cardif, demonstrating its www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901537 The Journal of Immunology 4561 unique role as a positive regulator of type I IFN production (17–19). It is clear that functions of TRAFs vary substantially among groups and between Drosophila and humans, thus it is of par- ticular interest to discover how these conserved adaptors in- creased in number and evolved their protein structures to adapt to the changing functions involved in TRAF-mediated path- ways, progressing from Drosophila to humans via intermediate species. One of the key intermediate species, amphioxus, rep- resents the oldest lineage of the chordata and contains 24 TRAFs, 48 TLRs, and a sophisticated TNF system not observed in other invertebrates (20). Thus, investigation into amphioxus TRAFs is not only of importance in revealing the novel func- tions of this complex defense systems in this primitive species but also will help to shed light on the evolution and develop- ment of TRAF-mediated signaling in humans. Materials and Methods Adults and embryos, cells, and reagents Downloaded from Adult Chinese amphioxus (Branchiostoma belcheri tsingtauense (Bbt)) were obtained from Qingdao, China. Samples of the blastula, gastrula, neurula, and larva were collected in the breeding season. Human HEK293T or Hela cells were grown in DMEM (Invitrogen) supplemented with 10% FCS and antibiotics. LPS of E. coli 0111:B4 was purchased from Sigma-Aldrich. FIGURE 1. Sequences analysis and comparison of amphioxus TRAF http://www.jimmunol.org/ Sequence data family. A, Domain topology comparison of 11 amphioxus TRAF1/2 mem- bers, which were arrayed on scaffold_21. B, Domain topology comparison The draft genome sequence of the amphioxus Branchiostoma floridae (Bf) of TRAFs among Drosophila, amphioxus, and human. Gene identification and the corresponding gene predictions can be accessed on the Branchios- was mainly performed with the HMMER2.0 plus SMART data set access- toma floridae version 1.0 website of the Joint Genome Institute, U.S. De- partment of Energy (http://genome.jgi-psf.org/Brafl1/Brafl1.home.html). Se- ing on the Branchiostoma floridae version 1.0 website of the Joint Genome quences of four amphioxus TRAFs were deposited in the National Center for Institute, U.S. Department of Energy (see Materials and Methods).
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