NEDD4 ubiquitinates TRAF3 to promote CD40-mediated AKT activation.

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

Index: Nat. Commun. 5 , 4513, (2014)

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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.