BS69, a specific adaptor in the latent membrane protein 1-mediated c-Jun N-terminal kinase pathway.
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.
Wan
Jun
J
Department of Biochemistry, Hong Kong University of Science & Technology, Clearwater Bay, Kowloon, Hong Kong.
Zhang
Wei
W
Wu
Liming
L
Bai
Ting
T
Zhang
Mingjie
M
Lo
Kwok-Wai
KW
Chui
Yiu-Loon
YL
Cui
Yan
Y
Tao
Qian
Q
Yamamoto
Masahiro
M
Akira
Shizuo
S
Wu
Zhenguo
Z
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D020798:Two-Hybrid System Techniques; D014763:Viral Matrix Proteins / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; C094763:ZMYND11 protein, human; D048031:JNK Mitogen-Activated Protein Kinases