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.
Mesh Terms:
Apoptosis, Cell Line, Contractile Proteins, Cytokines, HeLa Cells, Humans, Immunoprecipitation, Interferon Type I, JNK Mitogen-Activated Protein Kinases, Microfilament Proteins, Models, Biological, Signal Transduction, Ubiquitin-Conjugating Enzymes, Ubiquitins
EMBO Rep.
Date: Apr. 01, 2009
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