ISG15 modification of filamin B negatively regulates the type I interferon-induced JNK signalling pathway.
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.
Jeon
Young Joo
YJ
School of Biological Sciences, Seoul National University, 56-1 Shillim-dong, Kwanak-gu, Seoul 151-742, Republic of Korea.
Choi
Joon Seok
JS
Lee
Jung Yun
JY
Yu
Kyung Ryun
KR
Kim
Sangman Michael
SM
Ka
Seung Hyeun
SH
Oh
Kyu Hee
KH
Kim
Keun Il
KI
Zhang
Dong-Er
DE
Bang
Ok Sun
OS
Chung
Chin Ha
CH
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*
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