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Function in Vertebrates Receptor-Containing Adaptor Evidence for Evolving Toll-IL-1 Receptor-Containing Adaptor Molecule Function in Vertebrates This information is current as Con Sullivan, John H. Postlethwait, Christopher R. Lage, of September 30, 2021. Paul J. Millard and Carol H. Kim J Immunol 2007; 178:4517-4527; ; doi: 10.4049/jimmunol.178.7.4517 http://www.jimmunol.org/content/178/7/4517 Downloaded from References This article cites 60 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/178/7/4517.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 30, 2021 *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 © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Evidence for Evolving Toll-IL-1 Receptor-Containing Adaptor Molecule Function in Vertebrates1 Con Sullivan,* John H. Postlethwait,† Christopher R. Lage,* Paul J. Millard,‡ and Carol H. Kim2* In mammals, Toll-IL-1R-containing adaptor molecule 1 (TICAM1)-dependent TLR pathways induce NF-␬B and IFN-␤ re- sponses. TICAM1 activates NF-␬B through two different pathways involving its interactions with TNFR-associated factor 6 and receptor-interacting protein 1. It also activates IFN regulatory factor 3/7 through its interaction with TANK-binding kinase-1, leading to the robust up-regulation of IFN-␤. In this study, we describe the role of zebrafish (Danio rerio) TICAM1 in activating NF-␬B and zebrafish type I IFN. Zebrafish IFN is unique in that it cannot be categorized as being ␣-or␤-like. Through comprehensive sequence, phylogenetic, and syntenic analyses, we fully describe the identification of a zebrafish TICAM1 ortholog. Zebrafish TICAM1 exhibits sequence divergence from its mammalian orthologs and our data demonstrate that these sequence Downloaded from differences have functional consequences. Zebrafish TICAM1 activates zebrafish IFN; however, it does so in an apparently IFN regulatory factor 3/7-independent manner. Furthermore, zebrafish TICAM1 does not interact with zebrafish TNFR-associated factor 6, thus NF-␬B activation is dependent upon its interaction with receptor-interacting protein 1. Comparative genome analysis suggests that TICAM1 and TICAM2 evolved from a common vertebrate TICAM ancestor following a gene duplication event and that TICAM2 was lost in teleosts following the divergence of the rayfin and lobefin fishes 450 million years ago. These studies provide evidence, for the first time, of the evolving function of a vertebrate TLR pathway. The Journal of Immunology, http://www.jimmunol.org/ 2007, 178: 4517–4527. he recent discovery of a functional type I IFN in the ze- the signal cascade (reviewed in Refs. 10 and 11). One such adaptor brafish, Danio rerio, provided the first insight into how known as TIR domain-containing adaptor molecule 1 (TICAM1, T these essential antiviral cytokines evolved (1). Fish type I also known as TRIF) plays an essential role in TLR3 and TLR4 IFNs are unique in that they possess introns and, based upon phy- signaling, allowing for the up-regulation of IFN-␤ (12, 13). logenetic analyses, cluster away from mammalian type I IFNs (1, Mammalian TICAM1s are comprised of proline-rich N- and 2). The mechanisms underlying activation of fish type I IFNs have C-terminal domains and a central TIR domain essential for in- by guest on September 30, 2021 yet to be explored. In mammals, transcription of type I IFNs can be teractions with other TIR domains (12, 13). Each domain plays initiated by ligand activation of TLR3, TLR4, TLR7, TLR8, and an important role in signaling. The TIR domain is responsible TLR9 (3–9). TLRs transduce signals from extracellular stimuli for interacting with TLR3 or TICAM2. The N-terminal domain into the cell through interactions with adaptor molecules. Both can interact with TNFR-associated factor (TRAF)6 or form a TLRs and adaptor proteins possess Toll/IL-1R (TIR)3 domains that complex consisting of TANK-binding kinase (TBK)-1, IFN reg- facilitate the protein-protein interactions responsible for triggering ulatory factors (IRF)3 and 7 (IRF7), TRAF3, I␬B kinase-related kinase ␧, and NAK-associated protein-1 (14–21). The C-termi- nal domain interacts with receptor-interacting protein (RIP)1 *Department of Biochemistry, Microbiology, and Molecular Biology, University of and RIP3. Maine, Orono, ME 04469; †Institute of Neuroscience, University of Oregon, Eugene, OR 97403; and ‡Department of Chemical and Biological Engineering and The Lab- In this study, we report the identification of a novel zebrafish oratory for Surface Science and Technology, University of Maine, Orono, ME 04469 TICAM1 ortholog that exhibits unique structural and functional Received for publication September 6, 2006. Accepted for publication January features. Our results provide a glimpse into the evolutionary his- 10, 2007. tory of TLR-mediated type I IFN induction in a basally diverging The costs of publication of this article were defrayed in part by the payment of page vertebrate TICAM1-mediated pathway. Our findings suggest that charges. This article must therefore be hereby marked advertisement in accordance ␬ with 18 U.S.C. Section 1734 solely to indicate this fact. zebrafish TICAM1 activates NF- B and type I IFN through mech- 1 This work was supported in part by Grant R15AI049237-02 (to C.S., C.R.L., and anisms not observed in mammalian TICAM1 orthologs and that C.H.K.) from the National Institute for Allergy and Infectious Disease, Grant R01 while zebrafish type I IFN does not group with other avian or RR10715 (to J.H.P.) from the National Center for Research Resources, and Grant mammalian clades (1, 2), its TICAM1-dependent induction indi- R15AI065509-01 (to P.J.M.) from National Institute for Allergy and Infectious Dis- ease. All institutes are components of the National Institutes of Health and its contents cates the presence of this potent antiviral pathway in early are solely the responsibility of the authors and do not necessarily represent the official vertebrates. views of National Center for Research Resources or National Institutes of Health. 2 Address correspondence and reprint requests to Dr. Carol H. Kim, Department of Biochemistry, Microbiology, and Molecular Biology, 5735 Hitchner Hall, University of Maine, Orono, ME 04469. E-mail address: [email protected] Materials and Methods 3 Abbreviations used in this paper: TIR, Toll/IL-1R; TICAM, TIR domain-containing Nomenclature adaptor molecule; TRAF, TNFR-associated factor; TBK, TANK-binding kinase; IRF, IFN regulatory factor; RIP, receptor-interacting protein; ISRE, IFN-stimulated regu- Nomenclature rules for zebrafish, mouse, and human genes and proteins latory element; ZFL, zebrafish liver cell; RHIM, RIP homotypic interaction motif; follow different conventions. To minimize confusion in presenting these HA, hemagglutinin; poly(I:C), polyinosinic-polycytidylic acid. data, gene names will be presented in italicized capital letters (e.g., TICAM1) and protein names will be presented in standard capital letters Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 (e.g., TICAM1). www.jimmunol.org 4518 TICAM SIGNALING DIFFERS IN BASALLY DIVERGING VERTEBRATES DNA constructs Cell culture Zebrafish orthologs of TICAM1, RIP1, and TBK1 were identified through basic 293H cells (Invitrogen Life Technologies) were cultured at 37°C, 6% CO2 local alignment search tool sequence analyses of zebrafish genome and ex- in DMEM (high glucose) supplemented with 10% heat-inactivated FBS. pressed sequence tag databases using human and mouse orthologs and ZFL cells were grown in sealed vessels at 28°C in LDF medium, which available zebrafish sequence data. Each zebrafish ortholog was cloned and consists of 50% Leibovitz’s L-15 medium, 35% DMEM (high glucose), deposited in GenBank (zebrafish TICAM1, accession no. DQ848679; ze- and 15% F-12 nutrient mixture (Ham) supplemented with 5% heat-inacti- brafish RIP1, accession no. DQ848680; zebrafish TBK1, accession no. vated FBS, 0.5% heat-inactivated SeaGrow trout serum (East Coast Bio- DQ860098). Zebrafish IFN promoter was cloned from a DraI-digested, logics), 50 ng mlϪ1 mouse epidermal growth factor, and 1ϫ insulin-trans- zebrafish genomic DNA pool through nested PCR, according to the pro- ferrin-selenium-X. Unless otherwise noted, all culture products were tocol outlined in the GenomeWalker Universal kit (BD Clontech). First- purchased from Invitrogen Life Technologies. round PCR used primers AP1 (5Ј-GTAATACGACTCACTATAGGGC- 3Ј) and IFN PRO (5Ј-GTTATTATCCTGTATCGGCCAAGC-3Ј); nested, Luciferase reporter assays second-round PCR used primers AP2 (5Ј-ACTATAGGGCACGCGTGGT- 3Ј) and IFN PRO NESTED (5Ј-CATTCGCAAGTAGACGCAGAG-3Ј), 293H and ZFL cells were plated in 24-well plates (Corning) so that they and the product from the first round. Subsequently, the IFN promoter were 90–95% confluent on the day of transfection. Using Lipofectamine (GenBank accession no. DQ855952) was subcloned in pGL3-Basic (Pro- 2000 (Invitrogen Life Technologies), 400 ng of TICAM1 construct (mouse TICAM1 TRAF6 TICAM1, zebrafish TICAM1, or indicated deletion construct), 400 ng of mega) for use in luciferase reporter assays. Mouse , , and ␬ RIP1, along with the NF-␬B-luciferase reporter vector pBIIx and the IFN- reporter construct (NF- B: pBIIx-luc; ISRE: ISRE-luc; zebrafish minimal stimulated regulatory element (ISRE)-luciferase reporter vector ISRE-luc, Mx (ISRE) promoter: Mx187-luc; or zebrafish IFN promoter: pGL3-IFN were provided by R. Medzhitov (Yale University, New Haven, CT).
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