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* Department of Biochemistry, Microbiology, and Molecular Biology, University of Maine, Orono, ME 04469;
Institute of Neuroscience, University of Oregon, Eugene, OR 97403; and
Department of Chemical and Biological Engineering and The Laboratory for Surface Science and Technology, University of Maine, Orono, ME 04469
In mammals, Toll-IL-1R-containing adaptor molecule 1 (TICAM1)-dependent TLR pathways induce NF-
B and IFN-
responses. 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 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grant R15AI049237-02 (to C.S., C.R.L., and C.H.K.) from the National Institute for Allergy and Infectious Disease, Grant R01 RR10715 (to J.H.P.) from the National Center for Research Resources, and Grant R15AI065509-01 (to P.J.M.) from National Institute for Allergy and Infectious Disease. All institutes are components of the National Institutes of Health and its contents are solely the responsibility of the authors and do not necessarily represent the official 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: carolkim{at}maine.edu
3 Abbreviations used in this paper: TIR, Toll/IL-1R; TICAM, TIR domain-containing adaptor molecule; TRAF, TNFR-associated factor; TBK, TANK-binding kinase; IRF, IFN regulatory factor; RIP, receptor-interacting protein; ISRE, IFN-stimulated regulatory element; ZFL, zebrafish liver cell; RHIM, RIP homotypic interaction motif; HA, hemagglutinin; poly(I:C), polyinosinic-polycytidylic acid.
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