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Vol. 19, Issue 12, 5116-5130, December 2008

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Filamin B Serves as a Molecular Scaffold for Type I Interferon-induced c-Jun NH₂-terminal Kinase Signaling Pathway

Young Joo Jeon^*, Joon Seok Choi^*, Jung Yun Lee^*, Kyung Ryun Yu^*, Seung Hyeun Ka^*, Yongcheol Cho^*, Eui-Ju Choi, Sung Hee Baek^*, Jae Hong Seol^*, Dongeun Park^*, Ok Sun Bang^*, and Chin Ha Chung^*

*School of Biological Sciences, Seoul National University, Seoul 151-742, Korea; and School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea

Submitted June 9, 2008; Revised September 11, 2008; Accepted September 16, 2008
Monitoring Editor: Kunxin Luo

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 NH₂-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 IFN-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 IFN-dependent activation of JNK. Furthermore, filamin B promoted IFN-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.

Address correspondence to: Chin Ha Chung (chchung{at}snu.ac.kr)

Abbreviations used: ABD, actin-binding domain; GEF, guanine nucleotide-exchange factor; GSH, glutathione; H1, Hinge region 1; IFN, interferon; MAPK, mitogen-activated protein kinase; PARP, poly(ADP-ribose) polymerase; PBD, p21 (GTPase)-binding domain; TRAIL-R1, tumor necrosis factor-related apoptosis-inducing ligand-receptor 1.