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	Di-Feng Fang, Kun He, Na Wang, Zhi-Hong Sang, Xin Qiu, Guang Xu, Zhao Jian, Bing Liang, Tao Li, Hui-Yan Li, Ai-Ling Li, Tao Zhou, Wei-Li Gong, Baoli Yang, Michael Karin, Xue-Min Zhang, Wei-Hua Li
Journal	Nature communications (Nat Commun) Vol. 5 Pg. 4513 (Jul 29 2014) ISSN: 2041-1723 [Electronic] England
PMID	25072696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	CD40 Antigens Endosomal Sorting Complexes Required for Transport TNF Receptor-Associated Factor 3 Nedd4 Ubiquitin Protein Ligases Nedd4 protein, human Nedd4l protein, mouse Ubiquitin-Protein Ligases Oncogene Protein v-akt
Topics	Animals CD40 Antigens (metabolism) Endosomal Sorting Complexes Required for Transport (metabolism) Flow Cytometry Humans Immunity, Cellular (immunology) Immunoprecipitation Mass Spectrometry Mice Mice, Knockout Nedd4 Ubiquitin Protein Ligases Oncogene Protein v-akt (metabolism) RNA Interference Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Signal Transduction (immunology) TNF Receptor-Associated Factor 3 (metabolism) Ubiquitin-Protein Ligases (metabolism) Ubiquitination

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