IRF‐3 partners Bax in a viral‐induced dance macabre

In this issue of The EMBO Journal , Chattopadhyay et al (2010) describe a surprising new mechanism for how viral dsRNA detection by the RIG‐I/MAVS signalling complex can initiate apoptosis. Independent of its transcriptional function, a pool of interferon regulatory factor (IRF)‐3 activated downstream of MAVS can bind to and activate cytosolic Bax, resulting in Bax translocation to the mitochondria and initiation of the intrinsic apoptotic pathway. The essential requirement of the mitochondria localized protein MAVS (also known as IPS‐1, VISA or Cardif) to orchestrate the innate immune response following the detection of various cytoplasmic RNA molecules by the RNA helicases RIG‐I or Mda5 is well established (Yoneyama and Fujita, 2009). MAVS‐dependent signalling results in the activation of the transcription factors NF‐κB and IRFs, such as IRF‐3, which can act separately to induce inflammatory cytokines and chemokines or act together as part of an enhanceosome to induce type I interferons (IFNs).More recently, several groups have suggested that MAVS can also function in apoptosis induction to limit viral replication and spread. Activation of RIG‐I, and subsequent downstream MAVS signalling, can induce transcription of the pro‐apoptotic BH3‐only protein Noxa (and Puma) independent of p53, resulting in activation of the intrinsic apoptotic pathway, whereby Bax and Bak function to disrupt mitochondrial membrane integrity leading to cytochrome C release and formation of the caspase‐9 apoptosome (Figure 1A) (Besch et al , 2009 …