Filamin B: a scaffold for interferon signalling.

When cells become infected with a virus, they mount a coord inated antiviral response, a key component of which is the production of interferons (IFNs). This family of cytokines is present only in vertebrates , and mediates its antiviral effects both directly on infected cells and indirectly by activating other important effectors of the innate immune response, including natural killer cells, dendritic cells and macrophages (Sadler & Williams, 2008). There are three groups of IFNs: type I, type II and the poorly characterized type III. The type I IFNs are produced by virus-infected cells, whereas the only type II member—IFN-γ—is expressed in T cells and natural killer cells. The type I IFNs bind to a receptor complex at the cell surface—which is composed of two subunits, IFN-α receptor 1 (IFNAR1) and IFNAR2— and activate intra cellular signalling pathways, the best characterized of which is the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway. JAKs are tyrosine kinases that associate with the receptor complex and phosphorylate STAT proteins, which subsequently translocate to the nucleus and regulate the expression of IFN-stimulated genes (ISGs; Sadler & Williams, 2008). In addition to JAK–STAT signalling, IFNs activate other intra-cellular pathways, including mitogen-activated protein (MAP) kinase pathways. It has been shown recently that the c-Jun amino-terminal kinase (JNK) group of MAP kinases can mediate the IFN-α-induced apoptosis of cells (Yanase et al, 2005; Jeon et al, 2008). JNK signalling is required for normal development; however, it is also a major regulator of the response of cells to stress (Davis, 2000). The JNK pathway—similar to other MAP kinase pathways—features a core triple-kinase module consisting of a MAP kinase kinase kinase (MKKK), a MAP kinase kinase (MKK) and JNK. Members of the Rho family of small GTPases—including Rac1 and cell-division cycle 42 (Cdc42)—feed signals into this module. The specificity of signalling through the JNK pathway is partly mediated by scaffold proteins that bind to the components of the module, thereby directing their sub-cellular localization and restricting the signals that can activate the module (Davis, 2000). Two recent papers by Chung and colleagues—one of them in this issue of EMBO reports—have shed new light on how JNK signalling is regulated by type I IFNs (Jeon et al, 2008, 2009). They found that IFN-α activates a specific JNK signalling module consisting of the Rac1 GTPase, the mitogen-activated extracellular-signal-regulated kinase kinase 1 (MEKK1), MKK4 and JNK (Fig 1). Significantly, …