title: 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.
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 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.
authors.affiliation: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Eui-Soon
authors.initials: ES
authors.lastname: Park
authors.affiliation: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Seunga
authors.initials: S
authors.lastname: Choi
authors.affiliation: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Bongjin
authors.initials: B
authors.lastname: Shin
authors.affiliation: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Jungeun
authors.initials: J
authors.lastname: Yu
authors.affiliation: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Yu
authors.affiliation: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Jung-Me
authors.initials: JM
authors.lastname: Hwang
authors.affiliation: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Hyeongseok
authors.initials: H
authors.lastname: Yun
authors.affiliation: the Division of Life Science, Korea Basic Science Institute, Daejeon 305-333, Korea, and.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Chung
authors.affiliation: the Division of Life Science, Korea Basic Science Institute, Daejeon 305-333, Korea, and.
authors.forename: Jong-Soon
authors.initials: JS
authors.lastname: Choi
authors.affiliation: the Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.affiliation: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea, jrrho@cnu.ac.kr.
authors.forename: Jaerang
authors.initials: J
authors.lastname: Rho
mesh_terms: D001665:Binding Sites / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D008246:Lysophospholipids; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C060506:sphingosine 1-phosphate; D008239:Lysine; D013110:Sphingosine
keywords: Inflammation; NF-κB; Sphingosine 1-Phosphate (S1P); TNF Receptor-associated Factor (TRAF); TNFR; TRAF-interacting Protein; Tumor Necrosis Factor (TNF); Ubiquitylation (Ubiquitination)