The bacterial effector GarD shields Chlamydia trachomatis inclusions from RNF213-mediated ubiquitylation and destruction

Chlamydia trachomatis is the leading cause of sexually transmitted bacterial infections and a major threat to women's reproductive health in particular. This obligate intracellular pathogen resides and replicates within a cellular compartment termed an inclusion, where it is sheltered by unknown mechanisms from gamma -inter-feron (IFNy)-induced cell-autonomous host immunity. Through a genetic screen, we uncovered the Chla-mydia inclusion membrane protein gamma resistance determinant (GarD) as a bacterial factor protecting inclusions from cell-autonomous immunity. In IFNy-primed human cells, inclusions formed by garD loss -of-function mutants become decorated with linear ubiquitin and are eliminated. Leveraging cellular genome-wide association data, we identified the ubiquitin E3 ligase RNF213 as a candidate anti-Chlamydia protein. We demonstrate that IFNy-inducible RNF213 facilitates the ubiquitylation and destruction of GarD-deficient inclusions. Furthermore, we show that GarD operates as a cis-acting stealth factor barring RNF213 from targeting inclusions, thus functionally defining GarD as an RNF213 antagonist essential for chlamydial growth during IFNy-stimulated immunity.

Automated summary

Chlamydia trachomatis is a major threat to women's reproductive health and is the leading cause of sexually transmitted bacterial infections. In this study, researchers identified the GarD protein as a bacterial factor that protects the pathogen from host immune response. They also discovered the RNF213 protein as a potential anti-Chlamydia protein. This research provides insights into the mechanisms of Chlamydia infection and may contribute to the development of new treatments.