Filamin B serves as a molecular scaffold for type I interferon-induced c-Jun NH2-terminal kinase signaling pathway.
Type I interferons (IFNs) activate Janus tyrosine kinase-signal transducer and activator of transcription pathway for exerting pleiotropic biological effects, including antiviral, antiproliferative, and immunomodulatory responses. Here, we demonstrate that filamin B functions as a scaffold that links between activated Rac1 and a c-Jun NH(2)-terminal kinase (JNK) cascade module for mediating type I IFN signaling. Filamin B interacted with Rac1, mitogen-activated protein kinase kinase kinase 1, mitogen-activated protein kinase kinase 4, and JNK. Filamin B markedly enhanced IFNalpha-dependent Rac1 activation and the sequential activation of the JNK cascade members. Complementation assays using M2 melanoma cells revealed that filamin B, but not filamin A, is required for IFNalpha-dependent activation of JNK. Furthermore, filamin B promoted IFNalpha-induced apoptosis, whereas short hairpin RNA-mediated knockdown of filamin B prevented it. These results establish a novel function of filamin B as a molecular scaffold in the JNK signaling pathway for type I IFN-induced apoptosis, thus providing the biological basis for antitumor and antiviral functions of type I IFNs.
Jeon
Young Joo
YJ
School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
Choi
Joon Seok
JS
Lee
Jung Yun
JY
Yu
Kyung Ryun
KR
Ka
Seung Hyeun
SH
Cho
Yongcheol
Y
Choi
Eui-Ju
EJ
Baek
Sung Hee
SH
Seol
Jae Hong
JH
Park
Dongeun
D
Bang
Ok Sun
OS
Chung
Chin Ha
CH
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D022081:Cell Surface Extensions / Q000378:metabolism; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D064448:Filamins; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D034622:RNA Interference; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D003285:Contractile Proteins; D064448:Filamins; D007370:Interferon Type I; D008840:Microfilament Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein