title: Ubiquitin-associated domain-containing ubiquitin regulatory X (UBX) protein UBXN1 is a negative regulator of nuclear factor κB (NF-κB) signaling.
abstract: Excessive nuclear factor κB (NF-κB) activation should be precisely controlled as it contributes to multiple immune and inflammatory diseases. However, the negative regulatory mechanisms of NF-κB activation still need to be elucidated. Various types of polyubiquitin chains have proved to be involved in the process of NF-κB activation. Many negative regulators linked to ubiquitination, such as A20 and CYLD, inhibit IκB kinase activation in the NF-κB signaling pathway. To find new NF-κB signaling regulators linked to ubiquitination, we used a small scale siRNA library against 51 ubiquitin-associated domain-containing proteins and screened out UBXN1, which contained both ubiquitin-associated and ubiquitin regulatory X (UBX) domains as a negative regulator of TNFα-triggered NF-κB activation. Overexpression of UBXN1 inhibited TNFα-triggered NF-κB activation, although knockdown of UBXN1 had the opposite effect. UBX domain-containing proteins usually act as valosin-containing protein (VCP)/p97 cofactors. However, knockdown of VCP/p97 barely affected UBXN1-mediated NF-κB inhibition. At the same time, we found that UBXN1 interacted with cellular inhibitors of apoptosis proteins (cIAPs), E3 ubiquitin ligases of RIP1 in the TNFα receptor complex. UBXN1 competitively bound to cIAP1, blocked cIAP1 recruitment to TNFR1, and sequentially inhibited RIP1 polyubiquitination in response to TNFα. Therefore, our findings demonstrate that UBXN1 is an important negative regulator of the TNFα-triggered NF-κB signaling pathway by mediating cIAP recruitment independent of VCP/p97.
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Yu-Bo
authors: YB
authors: Wang
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Bo
authors: B
authors: Tan
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Rui
authors: R
authors: Mu
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Yan
authors: Y
authors: Chang
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Min
authors: M
authors: Wu
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Hai-Qing
authors: HQ
authors: Tu
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Yu-Cheng
authors: YC
authors: Zhang
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Sai-Sai
authors: SS
authors: Guo
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Xuan-He
authors: XH
authors: Qin
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Tao
authors: T
authors: Li
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Wei-Hua
authors: WH
authors: Li
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Ai-Ling
authors: AL
authors: Li
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
authors: Xue-Min
authors: XM
authors: Zhang
authors: From the Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China hyli@ncba.ac.cn.
authors: Hui-Yan
authors: HY
authors: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000074405:Valosin Containing Protein
chemical_list: C119724:AGFG1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D054852:Small Molecule Libraries; D014409:Tumor Necrosis Factor-alpha; C504037:UBXN1 protein, human; D008156:Luciferases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: Inflammation; NF-κB; Polyubiquitin Chain; Signal Transduction; Tumor Necrosis Factor (TNF); UBXN1; cIAPs