FIGURE 1: Proposed model for inhibition of the RIG-I signalosome by herpesvirus deconjugases. (A) Following binding to nucleic acids RIG-I undergoes a conformational change that exposes the CARD domains. Activated RIG-I binds to TRIM25, which promotes ubiquitination of the first CARD domain. 14-3-3 stabilizes the RIG-I-TRIM25 complex and promotes its translocation to MAVS where subsequent ubiquitin-regulated events lead to phosphorylation of the IRF3 transcription factor (p-IRF3). Activated IRF3 is translocated to the nucleus where it binds to IFN-response element (ISRE) leading to the activation of type I IFN response. Activation events are indicated by black arrows. (B) BPLF1 and the homologs encoded by other herpesviruses form a tri-molecular complex with 14-3-3 and TRIM25, which leads to activation and autoubiquitination of the ligases. A yet uncharacterized sequence of events results in failure to ubiquitinate RIG-I and functional inactivation of the RIG-I signalosome. Inhibitory events are indicated by red inverted T.