Involvement of Ymer in suppression of NF-kappaB activation by regulated interaction with lysine-63-linked polyubiquitin chain.
It is known that the cytoplasmic zinc finger protein A20 functionally dampens inflammatory signals and apoptosis via inhibition of NF-kappaB activation and biochemically acts as a unique ubiquitin-modifying protein with deubiquitinating activity and ubiquitin ligase activity. However, the molecular mechanisms of A20-modulated signal transduction that influence normal immune responses or tumor immunity have not been fully elucidated. Using a yeast two-hybrid system to search for proteins interacting with A20, we identified one novel binding protein, Ymer. Ymer, which has been reported to be highly phosphorylated on tyrosine residues via EGF stimulation, bound to lysine (K)-63-linked polyubiquitin chain on receptor-interacting serine/threonine-protein kinase 1 (RIP1), which is essential for NF-kappaB signaling in collaboration with A20. A luciferase assay showed that NF-kappaB signaling was down-regulated by overexpression of Ymer, whereas knock-down of Ymer up-regulated NF-kappaB signaling even without stimulation. These findings demonstrate that Ymer is likely to be a negative regulator for the NF-kappaB signaling pathway.
Bohgaki
Miyuki
M
Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
Tsukiyama
Tadasuke
T
Nakajima
Ayako
A
Maruyama
Satoru
S
Watanabe
Masashi
M
Koike
Takao
T
Hatakeyama
Shigetsugu
S
D002460:Cell Line; D004268:DNA-Binding Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism*; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D020798:Two-Hybrid System Techniques
C119724:AGFG1 protein, human; C478972:CCDC50 protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D025821:Polyubiquitin; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D008239:Lysine