title: 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.
abstract: 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-1β-induced NF-κB activation. Moreover, in vivo knockdown of DIGIRR by small interfering RNA significantly promoted the expression of IL-1β-stimulated proinflammatory cytokines (IL-6 and IL-1β) 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-1β-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 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.
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Yi-feng
authors.initials: YF
authors.lastname: Gu
authors.forename: Yu
authors.initials: Y
authors.lastname: Fang
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
authors.forename: Wei-ren
authors.initials: WR
authors.lastname: Dong
authors.forename: Li-xin
authors.initials: LX
authors.lastname: Xiang
authors.forename: Jian-zhong
authors.initials: JZ
authors.lastname: Shao
mesh_terms: D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D004625:Embryo, Nonmammalian; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D023701:Smegmamorpha / Q000235:genetics*; D023741:Takifugu / Q000235:genetics*; D023721:Tetraodontiformes / Q000235:genetics*; D051193:Toll-Like Receptors / Q000235:genetics*; D014162:Transfection; D015027:Zebrafish
chemical_list: D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors