Antiviral Innate Immunity


Fig 1. Overview of the RLR pathway (A) Schematic of the RLR signalosome assembly. RLRs form filaments upon cognate viral dsRNA binding. RLR filaments then cluster upon interaction with the E3 ligases RIPLET and TRIM65. In this clustered environment, the signaling domains (CARDs) of RLR form a homo-tetramer, which then nucleates filament formation of MAVS. The MAVS filament functions as a signaling platform to recruit further downstream signaling molecules (e.g. TRAFs) and to activate antiviral immune response. (B) Each step of receptor multimerization functions as a checkpoint to filter out self RNAs and to ensure that only non-self RNAs activate MAVS. Once the MAVS filament is nucleated, antiviral signal amplifies through MAVS filament propagation.


Pattern recognition receptors (PRRs) in the innate immune system are responsible for the early detection of pathogen invasion and activation of appropriate immunological responses. We are particularly interested in how a subset of PRRs, such as RIG-I-like receptors, robustly and accurately discriminate between cellular and viral RNAs during infection. It was traditionally thought that the dsRNA structure, which is often present in viral RNAs, provides sufficient means for PRRs to selectively recognize viral RNAs against the background of cellular RNAs. However, accumulating evidence suggests that the mechanism for viral RNA detection is more complex than a simple duplex binding, and the rules that separate self from non-self may not be as rigid as previously thought. Our mechanistic studies on the RIG-I-like receptors, in particular the discovery of their oligomerization and signaling mechanisms, have provided a new framework for understanding how these receptors detect viral RNAs during infection, how this recognition is coupled to antiviral signal activation, and how certain mutations lead to inappropriate recognition of self RNAs. Our current research focuses on (1) identities of self RNAs that trigger these receptors during pathologic conditions, (2) mechanisms by which these signaling complexes are resolved during the negative regulation of antiviral signaling, and (3) mechanisms of other antiviral RNA binding proteins, such as PKR, ZAP, and TRIM25.