A central part of the innate immune response is the detection of invading pathogens, such as viruses and bacteria, by recognition of pathogen-specific molecular markers. Nucleic acids are an example of such a marker, and are released into the host cell cytosol by invading viruses or may accumulate aberrantly in cells under stress conditions. ZBP1 is a cytosolic nucleic-acid sensing protein, which, when activated, recruits RIPK1 and RIPK3; proteins which initiate cell death as part of a wider immune response. Whilst this cell death pathway has been well characterised, a second component involving RIPK3-mediated inflammatory signalling had been suggested, although the underlying mechanisms were unknown.
In this work, Dr Ruoshi Peng and colleagues from the Gyrd-Hansen, Lu and Van den Eynde groups at Ludwig Oxford and collaborating institutes show that ZBP1 stimulates inflammatory signalling and cytokine production independently of the cell death pathway, and at a lower activation threshold. They determined that RIPK3 and RIPK1 have an essential role in this process as scaffolding proteins, acting to coordinate the response, and that a post-translational modification, ubiquitination, of this ZBP1-RIPK1-RIPK3 complex plays a key part in the proinflammatory pathway. This work suggests that ZBP1 has a dual function, inducing cell death or inflammatory signalling depending on the context.
They have also studied ZBP1’s role in the context of COVID-19. Using human lung epithelial cells, they demonstrate an upregulation of ZBP1 following SARS-CoV-2 infection, and suggest that this in turn stimulates the production of inflammatory cytokines, including CXCL10 and IL-6. This work therefore reveals a role for ZBP1 in the host response to SARS-CoV-2.
Read the full publication in EMBO reports.