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 |
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Authors: | Eui-Soon Park Seunga Choi Bongjin Shin Jungeun Yu Jiyeon Yu Jung-Me Hwang Hyeongseok Yun Young-Ho Chung Jong-Soon Choi Yongwon Choi Jaerang Rho |
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Institution: | From the ‡Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.;the §Division of Life Science, Korea Basic Science Institute, Daejeon 305-333, Korea, and ;the ¶Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 |
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Abstract: | 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 Lys63-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. |
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Keywords: | Inflammation NF-κ B Sphingosine 1-Phosphate (S1P) TNF Receptor-associated Factor (TRAF) Tumor Necrosis Factor (TNF) Ubiquitylation (Ubiquitination) TNFR Inflammation TRAF-interacting Protein |
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