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Molecular and Cellular Biology, January 2006, p. 448-456, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.448-456.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

BS69, a Specific Adaptor in the Latent Membrane Protein 1-Mediated c-Jun N-Terminal Kinase Pathway

Jun Wan,^1, Wei Zhang,^1, Liming Wu,¹ Ting Bai,¹ Mingjie Zhang,¹ Kwok-wai Lo,² Yiu-loon Chui,³ Yan Cui,⁴ Qian Tao,⁴ Masahiro Yamamoto,⁵ Shizuo Akira,⁵ and Zhenguo Wu^1*

Department of Biochemistry, Hong Kong University of Science & Technology,¹ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong,² Clinical Immunology Unit, Prince of Wales Hospital, The Chinese University of Hong Kong,³ Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong,⁴ Department of Host Defense, Osaka University, Osaka, Japan⁵

Received 31 August 2005/ Returned for modification 8 October 2005/ Accepted 21 October 2005

We previously demonstrated that the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) potently activates the cellular c-Jun N-terminal kinase (JNK) pathway by sequentially engaging an unknown adaptor, TRAF6, TAB1/TAK1, and JNKKs. We now show that BS69, a MYND domain-containing cellular protein, is the missing adaptor that bridges LMP1 and TRAF6, as the MYND domain and a separate region of BS69 bind to the carboxyl termini of LMP1 and TRAF6, respectively. While LMP1 promotes the interaction between BS69 and TRAF6, the complex formation between LMP1 and TRAF6 is BS69 dependent. A fraction of LMP1 and BS69 is constitutively colocalized in the membrane lipid rafts. Importantly, knockdown of BS69 by small interfering RNAs specifically inhibits JNK activation by LMP1 but not tumor necrosis factor alpha. Although overexpression of either BS69 or a mutant LMP1 without the cytoplasmic carboxyl tail is not sufficient to activate JNK, interestingly, when BS69 is covalently linked to the mutant LMP1, the chimeric protein restores the ability to activate JNK. This indicates that the recruitment and aggregation of BS69 is a prerequisite for JNK activation by LMP1.

These authors contributed equally to this work.

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