Liquid-liquid phase separation and rabies virus infection: viral factories and liquid condensates related to innate immunity

Le February 27 2023 at 14h00 Séminaire

Replication of Mononegavirales occurs in viral factories which form inclusions in the host-cell cytoplasm. For rabies virus (RABV), those inclusions are called Negri bodies (NBs). We demonstrated that NBs have characteristics similar to those of liquid condensates: they are spherical, they fuse to form larger structures, and they disappear upon hypotonic shock¹. 

Interestingly, RABV phosphoprotein P, which has a central role in NB formation, was known to inhibit interferon induction. Using a global mass spectrometry approach, we show that RABV P binds to TBK1, a kinase located at the crossroads of many interferon induction pathways, resulting in innate immunity inhibition. Mutations of TBK1 phosphorylation sites abolish P binding. Importantly, we demonstrate that upon RABV infection or detection of dsRNA by innate immunity sensors, TBK1 and its adaptor proteins NAP1 and SINTBAD form dynamic cytoplasmic condensates that have liquid properties. These condensates can form larger aggregates having ring-like structures in which NAP1 and TBK1 exhibit locally restricted movement. P binding to TBK1 interferes with the formation of these structures. This demonstrates that proteins of the signaling pathway leading to interferon induction transiently form liquid organelles that can be targeted by viruses².

 ¹ Nikolic et al. Negri bodies are viral factories with properties of liquid organelles. Nat Commun. 2017. 8(1):58.

² Scrima et al. Rabies virus P protein binds to TBK1 and interferes with the formation of innate immunity-related liquid condensates. Cell Rep. 2023 42(1):111949.