A prion-like trigger of antiviral signaling

Abstract

The MAVS protein plays a critical role in the assembly of an antiviral signaling complex on mitochondrial membranes. Hou et al. (2011) now report that virus infection induces a conformational change in MAVS, leading to the prion-like formation of functional self-aggregates that provide a sensitive trigger for antiviral signaling.

Figure 1. MAVS Forms Prion-like Aggregates to Activate Innate Immunity

Virus infection activates the RIG-I/MAVS pathway. Viral RNA binds to the C-terminal regulatory domain (RD) of RIG-I and induces a conformational change and dimerization. The central helicase domain is required for this process. The CARD domain of the RIG-I dimer then binds unanchored lysine-63 (K63) polyubiquitin chains and activates MAVS on the mitochondria membrane through the MAVS CARD domain. This interaction triggers a conformational switch of MAVS (changed color and shape of MAVS CARD in the diagram), which leads to the formation of MAVS aggregates on the mitochondrial membrane. MAVS aggregates are composed of MAVS polymers and potently activate downstream signaling cascade. Critical transcription factors IRF3 and NFκB are subsequently activated to induce the expression of interferon and other antiviral genes. MAVS aggregates behave like prions: they are partially resistant to detergent extraction and proteinase digestion and can efficiently self-propagate. The CARD domain of MAVS directly mediates the self-aggregation, and the transmembrane domain (TM) greatly facilitates MAVS aggregate formation on the mitochondria in vivo (left). Functional prion-like MAVS polymers can also form by self-aggregation in vitro in the absence of the TM domain (right). MAVS polymers formed in vitro can potently induce endogenous MAVS to form functional aggregates on the mitochondria from uninfected cells. This property closely resembles that of infectious prions.