title: NEDD4 ubiquitinates TRAF3 to promote CD40-mediated AKT activation.
abstract: CD40, a member of tumour necrosis factor receptor (TNFR) superfamily, has a pivotal role in B-cell-mediated immunity through various effector pathways including AKT kinase, but the signal transduction of CD40-meidated AKT activation is poorly understood. Here we report that the neural precursor cell expressed developmentally downregulated protein 4 (NEDD4), homologous to E6-AP Carboxyl Terminus family E3 ubiquitin ligase, is a novel component of the CD40 signalling complex. It has a key role in CD40-mediated AKT activation and is involved in modulating immunoglobulin class switch through regulating the expression of activation-induced cytidine deaminase. NEDD4 constitutively interacts with CD40 and mediates K63-linked ubiquitination of TNFR-associated factor3 (TRAF3). The ubiquitination of TRAF3 by NEDD4 is critical for CD40-mediated AKT activation. Thus, NEDD4 is a previously unknown component of the CD40 signalling complex necessary for AKT activation.
authors: 1] State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China [2].
authors: Di-Feng
authors: DF
authors: Fang
authors: 1] State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China [2].
authors: Kun
authors: K
authors: He
authors: 1] State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China [2].
authors: Na
authors: N
authors: Wang
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Zhi-Hong
authors: ZH
authors: Sang
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Xin
authors: X
authors: Qiu
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Guang
authors: G
authors: Xu
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Zhao
authors: Z
authors: Jian
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Bing
authors: B
authors: Liang
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Tao
authors: T
authors: Li
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Hui-Yan
authors: HY
authors: Li
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Ai-Ling
authors: AL
authors: Li
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Tao
authors: T
authors: Zhou
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Wei-Li
authors: WL
authors: Gong
authors: Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Baoli
authors: B
authors: Yang
authors: Laboratory of Gene Regulation and Signal Transduction, Cancer Center, Departments of Pharmacology and Pathology, University of California, San Diego, California 93093, USA.
authors: Michael
authors: M
authors: Karin
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Xue-Min
authors: XM
authors: Zhang
authors: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Institute of Basic Medical Sciences, Beijing 100850, China.
authors: Wei-Hua
authors: WH
authors: Li
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D019013:CD40 Antigens; D056827:Endosomal Sorting Complexes Required for Transport; D048008:TNF Receptor-Associated Factor 3; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D051058:Oncogene Protein v-akt