PUBLICATION
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
- Authors
- Gu, Y.F., Fang, Y., Jin, Y., Dong, W.R., Xiang, L.X., and Shao, J.Z.
- ID
- ZDB-PUB-110803-41
- Date
- 2011
- Source
- Journal of immunology (Baltimore, Md. : 1950) 187(5): 2514-30 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Base Sequence
- Blotting, Southern
- Embryo, Nonmammalian
- Humans
- Molecular Sequence Data
- Phylogeny
- Receptors, Interleukin-1/genetics*
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction/genetics*
- Smegmamorpha/genetics*
- Takifugu/genetics*
- Tetraodontiformes/genetics*
- Toll-Like Receptors/genetics*
- Transfection
- Zebrafish
- PubMed
- 21804011 Full text @ J. Immunol.
Citation
Gu, Y.F., Fang, Y., Jin, Y., Dong, W.R., Xiang, L.X., and Shao, J.Z. (2011) 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. Journal of immunology (Baltimore, Md. : 1950). 187(5):2514-30.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping