title: ISG15 modification of filamin B negatively regulates the type I interferon-induced JNK signalling pathway.
abstract: Interferon (IFN)-induced signalling pathways have essential functions in innate immune responses. In response to type I IFNs, filamin B tethers RAC1 and a Jun N-terminal kinase (JNK)-specific mitogen-activated protein kinase (MAPK) module--MEKK1, MKK4 and JNK--and thereby promotes the activation of JNK and JNK-mediated apoptosis. Here, we show that type I IFNs induce the conjugation of filamin B by interferon-stimulated gene 15 (ISG15). ISGylation of filamin B led to the release of RAC1, MEKK1 and MKK4 from the scaffold protein and thus to the prevention of sequential activation of the JNK cascade. By contrast, blockade of filamin B ISGylation by substitution of Lys 2467 with arginine or by knockdown of ubiquitin-activating enzyme E1-like (UBEL1) prevented the release of the signalling molecules from filamin B, resulting in persistent promotion of JNK activation and JNK-mediated apoptosis. These results indicate that filamin B ISGylation acts as a negative feedback regulatory gate for the desensitization of type I IFN-induced JNK signalling.
authors.affiliation: School of Biological Sciences, Seoul National University, 56-1 Shillim-dong, Kwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Jeon
authors.forename: Joon Seok
authors.initials: JS
authors.lastname: Choi
authors.forename: Jung Yun
authors.initials: JY
authors.lastname: Lee
authors.forename: Kyung Ryun
authors.initials: KR
authors.lastname: Yu
authors.forename: Sangman Michael
authors.initials: SM
authors.lastname: Kim
authors.forename: Seung Hyeun
authors.initials: SH
authors.lastname: Ka
authors.forename: Kyu Hee
authors.initials: KH
authors.lastname: Oh
authors.forename: Keun Il
authors.initials: KI
authors.lastname: Kim
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: Ok Sun
authors.initials: OS
authors.lastname: Bang
authors.forename: Chin Ha
authors.initials: CH
authors.lastname: Chung
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003285:Contractile Proteins / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D064448:Filamins; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D003285:Contractile Proteins; D016207:Cytokines; D064448:Filamins; D007370:Interferon Type I; D008840:Microfilament Proteins; D014452:Ubiquitins; C074034:ISG15 protein, human; C471622:UBE2L6 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D048031:JNK Mitogen-Activated Protein Kinases