期刊
EMBO REPORTS
卷 10, 期 4, 页码 374-380出版社
WILEY
DOI: 10.1038/embor.2009.23
关键词
apoptosis; filamin B scaffold; ISG15; JNK signalling pathway; type I interferon
资金
- Korea Research Foundation [KRF-2005-084-C00025]
- Korea Science and Engineering Foundation [M10533010001-05N3301-00100]
- National Research Foundation of Korea [2005-084-C00025] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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