CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Abstract

CASP4/caspase-11-dependent inflammasome activation is important for the clearance of various Gram-negative bacteria entering the host cytosol. Additionally, CASP4 modulates the actin cytoskeleton to promote the maturation of phagosomes harboring intracellular pathogens such as Legionella pneumophila but not those enclosing nonpathogenic bacteria. Nevertheless, this non-inflammatory role of CASP4 regarding the trafficking of vacuolar bacteria remains poorly understood. Macroautophagy/autophagy, a catabolic process within eukaryotic cells, is also implicated in the elimination of intracellular pathogens such as Burkholderia cenocepacia. Here we show that CASP4-deficient macrophages exhibit a defect in autophagosome formation in response to B. cenocepacia infection. The absence of CASP4 causes an accumulation of the small GTPase RAB7, reduced colocalization of B. cenocepacia with LC3 and acidic compartments accompanied by increased bacterial replication in vitro and in vivo. Together, our data reveal a novel role of CASP4 in regulating autophagy in response to B. cenocepacia infection.

Caspase‐11 counteracts mitochondrial ROS‐mediated clearance of Staphylococcus aureus in macrophages

“…Reduced secretion of IL‐1α and CXCL1/KC was found only in casp11 −/− macrophages (Fig C). We previously reported decreased CXCL1/KC production in casp11 −/− macrophages and mice in response to B. cenocepacia infection . Here, our data with MRSA support the idea of a general defect in CXCL1/KC production in the absence of CASP11.…”

“…We therefore conclude that CASP11 promotes MRSA persistence since it is required for the active dissociation of mitochondria away from the vicinity of MRSA-containing vacuoles. Contrary to Gram-positive bacteria, CASP11 promotes the clearance of Gram-negative bacteria by promoting phagosome-lysosome fusion [8,9,13]. Our data provide a new role for CASP11 in the pathogenesis of Gram-positive bacteria.…”

“…CASP11 has been shown to mediate cell migration and to modulate actin dynamics in response to bacterial infection . Since a higher percentage of MRSA is associated with mitochondria in casp11 −/− macrophages, we hypothesize that the inhibition of actin polymerization would facilitate co‐localization of MRSA‐containing phagosomes with mitochondria in WT cells.…”

Methylomic correlates of autophagy activity in cystic fibrosis

“…Macrophages from cystic fibrosis patients and mice allow the persistence and growth of B. cenocepacia, Pseudomonas, Staphylococcus, and non-tuberculosis mycobacteria [46,47]. This permissiveness is mainly due to weak autophagic activity as reports from our lab and other groups clearly demonstrated that autophagy is compromised in CF immune cells and epithelial cells [13,14,48]. We also showed that the expression of ATGs such as ATG5, ATG12, and ATG7 is significantly reduced in CF macrophages when compared to non-CF counterparts [13,35].…”

“…Corresponding secondary antibodies conjugated with horseradish peroxidase and in combination with enhanced chemiluminescence reagent (Amersham #RPN2209) were used to visualize protein bands. Densitometry analyses were performed by normalizing target protein bands to their respective GAPDH/β-actin loading control using ImageJ software as we previously described [30,34,35,48].…”