Guanylate-binding proteins

Guanylate-binding proteins aka GBPs:

Through functional genomics, we have identified the role of GBPs in inflammasome activation in mice and men. GBPs are IFN-inducible proteins targeting viruses, parasites and cytosolic bacteria, including Francisella novicida and orchestrating downstream responses. There are 11 Gbps in mice and 7 GBPs in humans and still a lot to be learned on these potent antimicrobial effectors!

Our major achievements in the field of GBPs:

2015: Discovery of murine Gbps as the IFN-inducible bacteriolytic proteins targeting cytosolic bacteria and triggering Aim2 inflammasome activation.

This project started with the discovery that Francisella was sensed in the macrophage cytosol by the inflammasome receptor sensing dsDNA. The question that arose at the time what to understand how genomic DNA was released from the cytosol of a bacterium into the host cytosol. We made the hypothesis that an IFN-inducible factors was involved and screened a siRNA library of 500 IFN-inducibles genes to identify Gbp2 and Gbp5 as factors required to trigger Aim2 inflammasome activation in response to F. novicida. We then collaborated with Petr Broz and Etienne Meunier to validate the findings in a mouse model of infection.

Meunier*, Wallet* et al. Nat Immunol 2015

2017: The Gbps beyond inflammasomes!

At this time, accumulating evidence were pointing to a link between Gbps and inflammasomes. We used a mouse model of tularemia to demonstrate that Gbps were key actors of immune innate responses against F. novicida in an inflammasome-dependent manner and independent manner. This work also demonstrated that most, if not all, of the antibacterial effect of IFN-gamma in vivo in this model was dependent on Gbps! Go Gbps! Wallet*, Benaoudia* et al. Plos Pathogens 2017

IFN-gamma controls F.novicida replication in a Gbp-dependent manner

Green means bacterial happily replicating in the macrophage cytosol. No green: the innate immune response keeps bacteria in check!

2018: GBPs in humans: A different story!

As a lab, we try as much as possible to work both in mice and in humans. And sometimes, biology works differently! Using primary human macrophages, siRNA and CRISPR-Cas9, we demonstrated that GBPs are also key in human cells infected with F. novicida but not to trigger the Aim2 inflammasome but to trigger activation of caspase-4. Indeed caspase-4 can sense the atypical F. novicida LPS while its murine counterpart, caspase-11 cannot! This is potentially why F. novicida is so lethal for rodents. Lagrange et al. Nature Communications 2018

hGBP2 targets F. novicida in the cytosol of a primary human macrophage

hGBP2 in green is targeting to cytosolic F. novicida bacteria (red) that have escaped the phagolysosomal degradation compartment labelled by Lamp1 (White). The nucleus from the primary human macrophage is stained in blue using DAPI.

Our collaborators on GBPs:

*Petr Broz's lab-Lausanne University, Switzerland

*Etienne Meunier's lab-IPBS-Toulouse, France

*Felix Randow's lab-MRC, Cambridge, UK

*Anders Sjöstedt's lab-Umeå University, Sweden