The identification of a new protein that coordinates the production of type I interferons (IFNs) in response to viral infection is reported in Cell this month.

The transcription factors NF-κB and IRF3 are essential for type I IFN production in response to RNA viruses, acting downstream of the receptors TLR3 and the recently identified RIG-I. However, the mechanisms by which RIG-I activates NF-κB and IRF3 are not clear, so the authors looked for other proteins containing caspase-recruitment domains (CARDs) similar to those of RIG-I that might be involved in this pathway. One protein with a single CARD at the amino terminus, a central proline-rich region and a hydrophobic transmembrane domain at the carboxyl terminus was identified and named mitochondrial antiviral signalling protein (MAVS) on the basis of the following properties.

Overexpression of MAVS by HEK293 cells activated a luciferase reporter under control of the IFN-α or IFN-β promoter, and MAVS was also shown to induce the production of endogenous IFN-β at both RNA and protein levels. This correlated with activation of both IRF3 and NF-κB. When the expression of endogenous MAVS was inhibited by RNA interference (RNAi), both NF-κB and IRF3 activation, and therefore IFN production, were abolished in response to the single-stranded RNA virus Sendai virus. The decrease in IFN production in response to viral RNA caused by MAVS RNAi increased viral titres and the sensitivity of cells to killing by vesicular stomatitis virus, showing the physiological importance of the MAVS-mediated innate antiviral pathway.

Some of the details of this pathway were elucidated by showing that whereas RNAi of MAVS blocked IFN-β induction by RIG-I, RNAi of RIG-I did not inhibit IFN-β induction by MAVS, which indicates that MAVS lies downstream of RIG-I. Further experiments showed that MAVS lies upstream of the IκB kinase IKK and the IRF3 kinase TBK1.

The transmembrane region of MAVS resembles that of several mitochondrial proteins, including apoptotic regulators of the BCL-2 family. Indeed, confocal microscopy and subcellular-fractionation experiments showed that MAVS co-localizes with the anti-apoptotic protein BCL-XL in the outer mitochondrial membrane. Mutant MAVS proteins that lacked the transmembrane domain and became cytosolic or that were targeted to different membrane locations, such as the plasma membrane or endoplasmic reticulum, had a markedly reduced ability to induce IFN-β, showing the importance of mitochondrial localization for the antiviral function of MAVS.

MAVS is therefore the first example of a mitochondrial protein with a role in innate immunity and that activates NF-κB and IRF3. The authors suggest that mitochondria can integrate signals from cellular stresses such as viral infection — with MAVS being ideally located to detect viral replication on intracellular membranes — to induce an immune or apoptotic response depending on the challenge.