Abstract
Interferon gamma (IFNγ) is the major proinflammatory cytokine conferring resistance to the intracellular vacuolar pathogen Toxoplasma gondii by inducing the destruction of the parasitophorous vacuole (PV). We previously identified TRIM21 as an IFNγ-driven E3 ubiquitin ligase mediating the deposition of ubiquitin around pathogen inclusions. Here, we show that TRIM21 knockout mice were highly susceptible to Toxoplasma infection, exhibiting decreased levels of serum inflammatory cytokines and higher parasite burden in the peritoneum and brain. We demonstrate that IFNγ drives recruitment of TRIM21 to GBP1-positive Toxoplasma vacuoles, leading to Lys63-linked ubiquitination of the vacuole and restriction of parasite early replication without interfering with vacuolar disruption. As seen in vivo, TRIM21 impacted the secretion of inflammatory cytokines. This study identifies TRIM21 as a previously unknown modulator of Toxoplasma gondii resistance in vivo thereby extending host innate immune recognition of eukaryotic pathogens to include E3 ubiquitin ligases.
Highlights
Toxoplasmosis is an infectious disease that is caused by an obligate intracellular parasite belonging to the phylum Apicomplexa called Toxoplasma gondii
While TRAF6 is crucially important for ubiquitin deposition at the parasitophorous vacuole (PV) leading to parasite restriction via p62-dependent guanylate binding proteins (GBPs)-mediated control in infected cells[22], it is still unclear what the role of tripartite motif protein 21 (TRIM21) is in this process
Using GBP1 as a marker for the host defence system, we showed that TRIM21 and GBP1 are recruited to the same type II Toxoplasma PVs in interferon γ (IFNγ)-stimulated mouse embryonic fibroblasts (MEFs) (Fig. 2a, Supplementary Fig. S5)
Summary
Toxoplasmosis is an infectious disease that is caused by an obligate intracellular parasite belonging to the phylum Apicomplexa called Toxoplasma gondii. Upon Toxoplasma infection, IFNγ mediates the deployment of a range of host defence molecules to the PV, leading to its disruption, autophagic elimination and inflammasome activation[9]. Central players in this defence mechanism are immunity-related GTPases (IRGs)[10,11,12,13] and guanylate binding proteins (GBPs)[14]. These large GTPases recognise vacuoles of intracellular pathogens for destruction and clearance, as well as govern the subsequent activation of the inflammasome[15,16,17,18,19,20,21]. TRIM21 has been reported to mediate recognition of viral RNA and DNA by the host sensors RIG-I and cGAS, respectively[37]
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