TIPE2 (Tumor Necrosis Factor α-induced Protein 8-like 2) Is a Novel Negative Regulator of TAK1 Signal

Abstract

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.

TIPE2 governs macrophage polarization via negative regulation of mTORC1

“…The role of TIPE2 in inhibiting the activation of M1 inflammation identified in the present study is important, due toits well-documented suppression of TAK1-IKKβ ( 16 ) and TLR4 activation ( 22 ). In the present study, the expression of TIPE2 was elevated in IL-4-induced M2 polarization.…”

“…The TLR-TAK1-IKKβ pathway promotes the transcription of M1-polarizing genes via IRF5 and NF-κB activation ( 18 – 20 ). TIPE2 disrupted TAK1-TGF-β-activated kinase 1 and MAP3K7-binding protein (TAB)1-TAB2 formation, and subsequently inhibited the activation of TAK1 and its downstream molecules ( 16 ). In the present study, BMDMs with mt-IKKβ (K171T), which represent constitutive activation of IKKβ, exhibited increased M1-like functional activation, even prior to LPS/IFNγ challenge.…”

“…Consequently, TIPE2-deficient mice have been demonstrated to exhibit increased M1 inflammation and resistance to M2 polarization, and the deficiency may retard systemic lupus erythematosus autoimmunity via macrophage polarization ( 14 , 15 ). Additionally, a cell-permeable TIPE2 protein exerted inhibitory effects on mitogen-activated protein kinase kinase kinase 7 (TAK1) phosphorylation ( 16 ). The present study assessed the role of TIPE2 in determining commitment to the process of macrophage activation and polarization.…”

Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets

“…Also, TIPE2 inhibits TAK1 in murine macrophages and this inhibition involves the interaction between TIPE2 amino acid 101–140 region and amino acid 200–291 region of the internal kinase domain of transforming growth factor-β-activated kinase 1 (TAK1) or mitogen-activated protein kinase kinase kinase 7 (MAP3K7) [99] . Thus, TIPE2 interferes with the formation of the TAK1-TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 (TAB1)-TAB2 complex, and inhibits TAK1 activation and its downstream signaling events resulting in the inhibition of the synthesis and release of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) [99] , important components of cytokine storm associated with development of sepsis. Further study has shown that TIPE2 promote the host resistance to Pseudomonas aeruginosa infection via inhibiting TAK1-mediated TLR signaling and inflammatory immune cell infiltration [100] .…”

TIPE2 Improves the immune tolerance of human amniotic mesenchymal stem cells

“…TIPE2 belongs to tumor necrosis factor alphainducible protein 8 (TNFAIP8) family and is one of the newly discovered negative regulators of body's immune balance (Sun et al 2008;Oho et al 2016). And it is an independent gene discovered in 2002 (Strausberg et al 2002).…”