Nicolas LOCKER

Tuesday, 12 April 2022 | 3.00 pm – ICGEB Trieste, ITALY

Professor of Virology, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK

Friends or Foes? The Many Routes Caliciviruses Use to Manipulate RNA Granules

(Host: A. Marcello)

To rapidly adapt to stresses such as viral infections, cells have evolved several mechanisms, which include the activation of stress response pathways and the innate immune response. These stress responses result in the rapid inhibition of translation and condensation of stalled mRNAs with RNA-binding proteins and signalling components into cytoplasmic biocondensates called stress granules (SGs). Increasing evidence suggests that SGs contribute to antiviral defence and thus viruses need to evade these threatening responses to propagate.

Caliciviruses are responsible for gastroenteritis outbreaks worldwide. We have examined how different caliciviruses interacts with stress pathways. We show that human norovirus infection represses host cell translation and induces a metabolic stress that is uncoupled from eIF2a signalling. Infection also results in a redistribution of the SG-scaffolding G3BP1 protein interactome, to prevent SG assembly. In contrast, feline calicivirus impairs SGs assembly by cleaving the scaffolding protein G3BP1. We also observed that uninfected bystander cells assembled G3BP1-positive granules, suggesting a paracrine response triggered by infection. We show that paracrine signalling from infected cells induces the formation of SG-like foci, that we named paracrine granules. They are linked to antiviral activity and exhibit specific kinetics of assembly-disassembly, and protein and RNA composition that are different from canonical SGs. We propose that this paracrine induction reflects a novel cellular defence mechanism to limit viral propagation and promote stress responses in bystander cells.

Overall, these results also illustrate novel and different strategies that related viruses have developed to avoid and manipulate the host stress response, promoting efficient replication.