RNF213-dependent lytic destruction of Chlamydia-containing vacuoles activates host cell death pathways.

Authors

Mary S Dickinson, Stephen C Walsh, Robert J Bastidas, Raphael H Valdivia, Jörn Coers

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 35. Pages e2606688123. Epub Aug 27, 2026.

Abstract

The cytokine gamma-interferon promotes antimicrobial cell-autonomous immunity by inducing hundreds of interferon-stimulated genes (ISGs). Among these ISGs is the ubiquitin E3 ligase RNF213 which protects host cells from a wide range of intracellular pathogens including the obligate intracellular bacterium Chlamydia. The human pathogen Chlamydia trachomatis normally employs its secreted virulence effector GarD to evade RNF213-mediated killing. However, in the absence of GarD, RNF213 is recruited to the vacuolar compartment in which C. trachomatis replicates, called the inclusion. Once localized to inclusions, RNF213 ubiquitylates unknown substrates associated with the inclusion membrane and eliminates C. trachomatis through mechanisms that are not yet defined. Ubiquitylation of pathogen-containing vacuoles often results in xenophagy, an autophagy-related defense program. Here, we show that although inclusions can be degraded via xenophagy, this pathway is dispensable for RNF213-dependent inhibition of C. trachomatis replication. In addition to xenophagy, we find that RNF213 targeting can lead to antimicrobial inclusion lysis, thereby releasing bacteria into the host cell cytosol and triggering host cell death. Two cell death pathways occur downstream from RNF213-dependent inclusion rupture: a rapid cell death that despite its apoptosis-like morphology occurs independent of the apoptosis effectors caspase-3 and caspase-7 and instead requires the secreted C. trachomatis protease CPAF, and a slow cell death that is independent of CPAF and instead requires the cytosolic proinflammatory pattern-recognition receptors RIG-I or STING. Thus, RNF213-driven lysis of pathogen-containing vacuoles represents a previously unrecognized mechanism by which RNF213 mediates host defense and triggers a host-pathogen battle over cytosolic immune activation.

PMID:
42658761
Bibliographic data and abstract were imported from PubMed on 28 Aug 2026.

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