A novel mechanism for regulation of the type I IFN response by herpesvirus deconjugases

• Main Authors: Soham Gupta, Päivi Ylä-Anttila, Maria G. Masucci
• Format: Article
• Language: English
• Published: Shared Science Publishers OG 2018-04-01
• Series: Microbial Cell
• Subjects: Epstein-Barr virus; Herpesvirus; deconjugase; RIG-I signalosome; type I IFN
• Online Access: http://microbialcell.com/researcharticles/a-novel-mechanism-for-regulation-of-the-type-i-ifn-response-by-herpesvirus-deconjugases/

Upon infection, viral nucleic acids are recognized by germline-encoded pattern-recognition receptors (PRRs), and cytosolic retinoic acid-inducible gene I (RIG-I)-like helicases (RLHs) that initiate signaling pathways resulting in the production of type I IFN and pro-inflammatory cytokines. Binding of RIG-I to viral nucleic acids triggers the formation of the RIG-I signalosome where RIG-I is ubiquitinated by the TRIM25 ligase and, with the help of 14-3-3 scaffolds, further translocated to mitochondrial anti-viral signalling proteins (MAVS). Subsequent ubiquitination-mediated events trigger transcriptional activation of the effectors of innate immunity. We have found a new mechanism by which herpesviruses interfere with this signalling pathway to favour the establishment of latency and promote virus replication. The cysteine protease encoded in the conserved N-terminal domain of the herpesvirus large tegument protein binds to 14-3-3 proteins and forms a tri-molecular complex with TRIM25, promoting the activation and autoubiquitination of the ligase. RIG-I is recruited to the complex but its ubiquitination is drastically reduced, which effectively inactivates downstream signalling and blocks the type I IFN response.