An Epstein-Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation

Mol Cell. 2023 Jul 6;83(13):2367-2386.e15. doi: 10.1016/j.molcel.2023.05.018. Epub 2023 Jun 12.


Epstein-Barr virus (EBV) causes infectious mononucleosis, triggers multiple sclerosis, and is associated with 200,000 cancers/year. EBV colonizes the human B cell compartment and periodically reactivates, inducing expression of 80 viral proteins. However, much remains unknown about how EBV remodels host cells and dismantles key antiviral responses. We therefore created a map of EBV-host and EBV-EBV interactions in B cells undergoing EBV replication, uncovering conserved herpesvirus versus EBV-specific host cell targets. The EBV-encoded G-protein-coupled receptor BILF1 associated with MAVS and the UFM1 E3 ligase UFL1. Although UFMylation of 14-3-3 proteins drives RIG-I/MAVS signaling, BILF1-directed MAVS UFMylation instead triggered MAVS packaging into mitochondrial-derived vesicles and lysosomal proteolysis. In the absence of BILF1, EBV replication activated the NLRP3 inflammasome, which impaired viral replication and triggered pyroptosis. Our results provide a viral protein interaction network resource, reveal a UFM1-dependent pathway for selective degradation of mitochondrial cargo, and highlight BILF1 as a novel therapeutic target.

Keywords: MAVS; NLRP3 inflammasome; UFMylation; antiviral defense; gamma-herpesvirus; herpesvirus; interactome; mitochondrial-derived vesicles; viral evasion; virus/host interaction.

MeSH terms

  • Epstein-Barr Virus Infections* / genetics
  • Herpesvirus 4, Human* / genetics
  • Humans
  • Inflammasomes / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Protein Interaction Maps


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein