The effector IpaH1.4 facilitates RNF213 degradation and protects cytosolic bacteria against interferon-induced ubiquitylation.

A central signal that marshals host defense against many infections is the lymphocyte-derived cytokine interferon-gamma (IFNγ). The IFNγ receptor is expressed on most human cells and its activation leads to the expression of antimicrobial proteins that execute diverse cell-autonomous immune programs. One such immune program consists of the sequential detection, ubiquitylation, and destruction of intracellular pathogens.

Pyroptosis in defense against intracellular bacteria.

Pathogenic microbes invade the human body and trigger a host immune response to defend against the infection. In response, host-adapted pathogens employ numerous virulence strategies to overcome host defense mechanisms. As a result, the interaction between the host and pathogen is a dynamic process that shapes the evolution of the host's immune response.

LPS-aggregating proteins GBP1 and GBP2 are each sufficient to enhance caspase-4 activation both in cellulo and in vitro.

The gamma-interferon (IFNγ)-inducible guanylate-binding proteins (GBPs) promote host defense against gram-negative cytosolic bacteria in part through the induction of an inflammatory cell death pathway called pyroptosis. To activate pyroptosis, GBPs facilitate sensing of the gram-negative bacterial outer membrane component lipopolysaccharide (LPS) by the noncanonical caspase-4 inflammasome. There are seven human GBP paralogs, and it is unclear how each GBP contributes to LPS sensing and pyroptosis induction.

Interferon-Inducible E3 Ligase RNF213 Facilitates Host-Protective Linear and K63-Linked Ubiquitylation of Toxoplasma gondii Parasitophorous Vacuoles.

The obligate intracellular protozoan pathogen Toxoplasma gondii infects a wide range of vertebrate hosts and frequently causes zoonotic infections in humans. Whereas infected immunocompetent individuals typically remain asymptomatic, toxoplasmosis in immunocompromised individuals can manifest as a severe, potentially lethal disease, and congenital infections are associated with adverse pregnancy outcomes. The protective immune response of healthy individuals involves the production of lymphocyte-derived cytokines such as interferon gamma (IFN-γ), which elicits cell-autonomous immunity in host cells.

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-interferon (IFNγ)-induced cell-autonomous host immunity. Through a genetic screen, we uncovered the Chlamydia inclusion membrane protein gamma resistance determinant (GarD) as a bacterial factor protecting inclusions from cell-autonomous immunity.

SNX10 and caspase-5 sort out endosomal LPS for a gut-wrenching Slug-fest.

Endosomes are important cellular compartments for sorting internalized cargo and immune sensing. In this issue, Wang et al describe a novel signaling pathway induced by endocytosed bacterial outer membrane vesicles, where sorting nexin 10 and caspase-5 act at the endosome to promote cytosolic exposure of LPS and initiate signaling to alter epithelial layer integrity. This study presents the first example of a specialized function for caspase-5, distinct from the inflammasome function executed by the closely related paralog caspase-4.

Proximity-dependent proteomics of the Chlamydia trachomatis inclusion membrane reveals functional interactions with endoplasmic reticulum exit sites.

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infection, responsible for millions of infections each year. Despite this high prevalence, the elucidation of the molecular mechanisms of Chlamydia pathogenesis has been difficult due to limitations in genetic tools and its intracellular developmental cycle. Within a host epithelial cell, chlamydiae replicate within a vacuole called the inclusion.