Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) negatively regulates the TRAF2 ubiquitin-dependent pathway by suppressing the TRAF2-sphingosine 1-phosphate (S1P) interaction.
The signaling pathway downstream of TNF receptor (TNFR) is involved in the induction of a wide range of cellular processes, including cell proliferation, activation, differentiation, and apoptosis. TNFR-associated factor 2 (TRAF2) is a key adaptor molecule in TNFR signaling complexes that promotes downstream signaling cascades, such as nuclear factor-κB (NF-κB) ... and mitogen-activated protein kinase activation. TRAF-interacting protein (TRIP) is a known cellular binding partner of TRAF2 and inhibits TNF-induced NF-κB activation. Recent findings that TRIP plays a multifunctional role in antiviral response, cell proliferation, apoptosis, and embryonic development have increased our interest in exploring how TRIP can affect the TNFR-signaling pathway on a molecular level. In our current study, we demonstrated that TRIP is negatively involved in the TNF-induced inflammatory response through the down-regulation of proinflammatory cytokine production. Here, we demonstrated that the TRAF2-TRIP interaction inhibits Lys(63)-linked TRAF2 ubiquitination by inhibiting TRAF2 E3 ubiquitin (Ub) ligase activity. The TRAF2-TRIP interaction inhibited the binding of sphingosine 1-phosphate, which is a cofactor of TRAF2 E3 Ub ligase, to the TRAF2 RING domain. Finally, we demonstrated that TRIP functions as a negative regulator of proinflammatory cytokine production by inhibiting TNF-induced NF-κB activation. These results indicate that TRIP is an important cellular regulator of the TNF-induced inflammatory response.
Mesh Terms:
Binding Sites, Cytokines, Gene Expression, HEK293 Cells, HeLa Cells, Humans, Immunoblotting, Lysine, Lysophospholipids, NF-kappa B, Protein Binding, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Sphingosine, TNF Receptor-Associated Factor 2, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Tumor Necrosis Factor-alpha, Ubiquitin, Ubiquitination
Binding Sites, Cytokines, Gene Expression, HEK293 Cells, HeLa Cells, Humans, Immunoblotting, Lysine, Lysophospholipids, NF-kappa B, Protein Binding, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Sphingosine, TNF Receptor-Associated Factor 2, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Tumor Necrosis Factor-alpha, Ubiquitin, Ubiquitination
J. Biol. Chem.
Date: Apr. 10, 2015
PubMed ID: 25716317
View in: Pubmed Google Scholar
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