TIPE2 (Tumor Necrosis Factor α-induced Protein 8-like 2) Is a Novel Negative Regulator of TAK1 Signal.
TIPE2 (TNF-α-induced protein 8-like 2) is a novel death effector domain protein and is a negative regulator of the innate and adaptive immune response. Although it has been demonstrated that caspase-8 contributes to the negative regulation of TIPE2, the negative regulatory mechanism is not entirely understood. Here, we demonstrate that TIPE2 interacts with TGF-β-activated kinase 1 (TAK1), a crucial regulatory molecule of inflammatory and immune signals, and consequently acts as a powerful negative regulator of TAK1. The interaction between endogenous TIPE2 and TAK1 was observed in RAW264.7 macrophage-like cells and mouse primary cells derived from spleen and thymus. The TIPE2 amino acid 101-140 region interacted with TAK1 by binding to the amino acid 200-291 region of the internal kinase domain of TAK1. TIPE2 interfered with the formation of the TAK1-TAB1-TAB2 complex and subsequently inhibited activation of TAK1 and its downstream molecules. Importantly, silencing TIPE2 through RNA interference attenuated the inhibitory action of TIPE2 on LPS- and TNF-α-stimulated TAK1 activity. Exogenous TIPE2 101-140, the region that interacts with TAK1, also inhibited LPS- and TNF-α-stimulated NF-κB reporter activity. Interestingly, cell-permeable TIPE2 protein maintained its binding ability with TAK1 and exhibited the same inhibitory action of native TIPE2 on TLR4 signaling in vitro Thus, cell-permeable TIPE2 protein is a potential candidate for intracellular protein therapy for TAK1-related diseases. The present study demonstrates that TIPE2 acts as a novel negative regulator of inflammatory and immune responses through TAK1 signaling.
From the Department of Applied Biological Sciences, College of Bioresource Sciences, Nihon University, Fujisawa City, Kanagawa 252-0880, Japan.
Michitaka
M
Oho
From the Department of Applied Biological Sciences, College of Bioresource Sciences, Nihon University, Fujisawa City, Kanagawa 252-0880, Japan.
Risa
R
Nakano
From the Department of Applied Biological Sciences, College of Bioresource Sciences, Nihon University, Fujisawa City, Kanagawa 252-0880, Japan.
Ryutarou
R
Nakayama
From the Department of Applied Biological Sciences, College of Bioresource Sciences, Nihon University, Fujisawa City, Kanagawa 252-0880, Japan.
Wataru
W
Sakurai
From the Department of Applied Biological Sciences, College of Bioresource Sciences, Nihon University, Fujisawa City, Kanagawa 252-0880, Japan.
Azusa
A
Miyamoto
From the Department of Applied Biological Sciences, College of Bioresource Sciences, Nihon University, Fujisawa City, Kanagawa 252-0880, Japan.
Yoshikazu
Y
Masuhiro
From the Department of Applied Biological Sciences, College of Bioresource Sciences, Nihon University, Fujisawa City, Kanagawa 252-0880, Japan hanazawa@brs.nihon-u.ac.jp.
Shigemasa
S
Hanazawa
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D000067996:RAW 264.7 Cells; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C529002:TIPE2 protein, mouse; C531463:Tab1 protein, mouse; C498761:Tab2 protein, mouse; C493487:Tlr4 protein, mouse
cell-penetrating peptide (CPP); immunology; inflammation; signal transduction; tumor necrosis factor (TNF)