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IL-1 Signaling Member Serving As A Discovery of the DIGIRR Gene from Teleost Fish: A Novel Toll−IL-1 Receptor Family Member Serving as a Negative Regulator of IL-1 Signaling This information is current as of October 1, 2021. Yi-feng Gu, Yu Fang, Yang Jin, Wei-ren Dong, Li-xin Xiang and Jian-zhong Shao J Immunol 2011; 187:2514-2530; Prepublished online 29 July 2011; doi: 10.4049/jimmunol.1003457 Downloaded from http://www.jimmunol.org/content/187/5/2514 Supplementary http://www.jimmunol.org/content/suppl/2011/07/29/jimmunol.100345 Material 7.DC1 http://www.jimmunol.org/ References This article cites 87 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/187/5/2514.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 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 © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Discovery of the DIGIRR Gene from Teleost Fish: A Novel Toll–IL-1 Receptor Family Member Serving as a Negative Regulator of IL-1 Signaling Yi-feng Gu, Yu Fang, Yang Jin, Wei-ren Dong, Li-xin Xiang, and Jian-zhong Shao Toll–IL-1R (TIR) family members play crucial roles in a variety of defense, inflammatory, injury, and stress responses. Although they have been widely investigated in mammals, little is known about TIRs in ancient vertebrates. In this study, we report a novel double Ig IL-1R related molecule (DIGIRR) from three model fish (Tetraodon nigroviridis, Gasterosteus aculeatus, and Takifugu rubripes), adding a previously unknown homolog to the TIR family. This DIGIRR molecule contains two Ig-like domains in the extracellular region, one Arg-Tyr–mutated TIR domain in the intracellular region, and a unique subcellular distribution within the Golgi apparatus. These characteristics distinguish DIGIRR from other known family members. In vitro injection of DIGIRR into zebrafish embryos dramatically inhibited LPS-induced and IL-1b–induced NF-kB activation. Moreover, in vivo knockdown Downloaded from of DIGIRR by small interfering RNA significantly promoted the expression of IL-1b–stimulated proinflammatory cytokines (IL-6 and IL-1b) in DIGIRR-silenced liver and kidney tissues and in leukocytes. These results strongly suggest that DIGIRR is an important negative regulator of LPS-mediated and IL-1b–mediated signaling pathways and inflammatory responses. The Arg- Tyr–mutated site disrupted the signal transduction ability of DIGIRR TIR. Evolutionally, we propose a hypothesis that DIGIRR and single Ig IL-1R related molecule (SIGIRR) might originate from a common ancient IL-1R–like molecule that lost one (in DIGIRR) or two (in SIGIRR) extracellular Ig-like domains and intracellular Ser and Arg-Tyr amino acids. DIGIRR might be an http://www.jimmunol.org/ evolutionary “transitional molecule” between IL-1R and SIGIRR, representing a shift from a potent receptor to a negative regulator. These results help define the evolutionary history of TIR family members and their associated signaling pathways and mechanisms. The Journal of Immunology, 2011, 187: 2514–2530. he Toll–IL-1R (TIR) superfamily encompasses a group of presence of microorganisms and activate a complex, multifaceted structurally homologous proteins that are essential for the cellular defense response (9–14). The Ig domain-containing sub- T initiation of innate host defenses against infection, aller- group includes the IL-1R type I (IL-1RI) (15) and its accessory gic and nonallergic inflammation, injury, and stress (1–4). Mem- protein (IL-1RAcP) (16), the IL-18Rs (IL-18Ra and IL-18Rb) by guest on October 1, 2021 bers are distinguished by the presence of a conserved intracellular (17, 18), the regulatory receptors T1/ST2 (19–21), and a number TIR domain that signals to the NF-kB, MAPK, and AP-1 path- of orphan receptors, including three Ig IL-1R related molecule-1 ways (5–7). This superfamily can be further divided into two and molecule-2 (TIGIRR-1/2) (22), the IL-1R related protein subgroups on the basis of its extracellular domains: the leucine- 2 (IL-1Rrp2) (23), and the single Ig IL-1R related molecule rich repeats receptors, such as TLRs (1), and the Ig domain- (SIGIRR) (24–27). The pleiotropic cytokine IL-1 is known to be containing receptors (8). The TLRs function as sensors for the involved in a variety of immune activities, such as T cell and B cell proliferation and differentiation, as well as IL-2 and IL-6 College of Life Sciences, Zhejiang University, Hangzhou 310058, People’s Republic production (28, 29). When agonist IL-1 binds to the IL-1R com- of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, plex, it initiates an amplification cascade of innate resistance, Hangzhou 310058, People’s Republic of China; and Key Laboratory of Animal contributes to the activation of adaptive immunity, and modulates Epidemic Etiology and Immunology Prevention of the Ministry of Agriculture, Hangzhou 310058, People’s Republic of China inflammatory reactions (29, 30). Received for publication October 20, 2010. Accepted for publication June 20, 2011. A series of negative regulators of IL-1 signaling pathways has been identified, including IL-1R–associated kinase (IRAK)-M This work was supported by grants from the National Basic Research Program of China (973) (2006CB101805), the Hi-Tech Research and Development Program of (31), MyD88s (32), SOCS-1 (33), type II IL-1R (IL-1RII) (34, China (863) (2008AA09Z409), the National Natural Science Foundation of China 35), T1/ST2 (36), and SIGIRR (24–27), which suppress IL-1 (30871936, 31072234), and the Science and Technology Foundation of Zhejiang Province (2007C12011). signaling pathways through different mechanisms. Among these inhibitors, IL-1RII, T1/ST2, and SIGIRR are members of the IL- The data presented in this article have been submitted to GenBank under accession numbers EF095151, EU305619, and EU360722. 1R family. In addition, both IL-1RII and T1/ST2 receptors contain Address correspondence and reprint requests to Prof. Jian-zhong Shao and Dr. Li-xin three Ig-like domains, whereas SIGIRR contains a single Ig-like Xiang, Zhejiang University, Hangzhou 310058, Zhejiang, People’s Republic of domain. An intriguing issue is whether double Ig domain recep- China. E-mail addresses: [email protected] and [email protected] tors exist and whether they act as positive or negative regulators. The online version of this article contains supplemental material. Although the TIR superfamily has been widely studied in Abbreviations used in this article: DIG, digoxigenin; DIGIRR, double Ig IL-1R re- mammals, little is known about its existence, occurrence, and lated molecule; EST, expressed sequence tag; IL-1RAcP, IL-1R accessory protein; IL-1RI, type I IL-1R; IL-1RII, type II IL-1R; IL-1Rrp2, IL-1R related protein 2; function in lower vertebrates like fish. In recent years, a number of IRAK, IL-1R–associated kinase; ORF, open reading frame; RNAi, RNA interference; IL-1 family members and TIR-containing receptors, such as IL- SIGIRR, single Ig IL-1R related molecule; siRNA, small interfering RNA; TIGIRR, 1b, IL-18, IL-1RI, IL-1RII, IL-1RAcP, ST2L, and TLR1–TLR23, three Ig IL-1R related molecule; TIR, Toll–IL-1R; UTR, untranslated region. have been identified in fish (37–47), indicating the presence of IL- Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 1 and TIR signaling. However, few reports regarding the negative www.jimmunol.org/cgi/doi/10.4049/jimmunol.1003457 The Journal of Immunology 2515 regulators in TIR signaling are available, except for a Tollip ho- boundaries) were elucidated by comparing DIGIRR cDNAs with genome molog recently identified from Oncorhynchus mykiss (48). In- sequences, and illustrations were drawn using GeneMaper 2.5 (http:// vestigating the extent of the negative feedback mechanisms in genemaper.googlepages.com). Selected species included Gallus gallus, T. nigroviridis, G. aculeatus, T. rubripes, Homo sapiens, Mus musculus, ancient vertebrates such as fishes and the evolutionary changes and Rattus norvegicus. The potential functional motifs in the DIGIRR that have occurred in this cytokine regulatory network during protein were analyzed by PROSITE (50), SMART database (51), and the vertebrate evolution would be intriguing. TMHMM (http://www.cbs.dtu.dk/services/TMHMM-2.0/) program (52, In the current study, the TIRs were identified in three fish species, 53). The signal peptidase cleavage sites were predicted with SignalP 3.0 (http://www.cbs.dtu.dk/services) (54). BLAST was used to examine the Tetraodon nigroviridis, Gasterosteus aculeatus,andTakifugu deduced amino acid sequence against the SwissProt protein database rubripes, and a novel family member, named double Ig IL-1R (http://www.expasy.org/tools/blast/) (55). Percentage amino acid sequence related molecule (DIGIRR), was successfully characterized. Phy- identity was calculated using the MEGALIGN program from DNASTAR, logenetic analysis revealed that fish DIGIRR was homologous and a multiple alignment was generated using the ClustalW program to SIGIRR, but distinct in both protein structure and subcellu- (version 1.83) (56). lar localization. In vivo and in vitro functional characterization Southern blot analysis demonstrated that DIGIRR served as a negative regulator of IL-1– mediated signaling.
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