Survival of Mycobacteria in Macrophages Is Mediated by Coronin 1-Dependent Activation of Calcineurin

Abstract

Pathogenic mycobacteria survive within macrophages by avoiding lysosomal delivery, instead residing in mycobacterial phagosomes. Upon infection, the leukocyte-specific protein coronin 1 is actively recruited to mycobacterial phagosomes, where it blocks lysosomal delivery by an unknown mechanism. Analysis of macrophages from coronin 1-deficient mice showed that coronin 1 is dispensable for F-actin-dependent processes such as phagocytosis, motility, and membrane ruffling. However, upon mycobacterial infection, coronin 1 was required for activation of the Ca(2+)-dependent phosphatase calcineurin, thereby blocking lysosomal delivery of mycobacteria. In the absence of coronin 1, calcineurin activity did not occur, resulting in lysosomal delivery and killing of mycobacteria. Furthermore, blocking calcineurin activation with cyclosporin A or FK506 led to lysosomal delivery and intracellular mycobacterial killing. These results demonstrate a role for coronin 1 in activating Ca(2+) dependent signaling processes in macrophages and reveal a function for calcineurin in the regulation of phagosome-lysosome fusion upon mycobacterial infection.

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

“…What seems clear at this stage is that MA and cholesterol may not be recognized as individual haptens, but rather as molecular clusters forming multi-faceted surfaces, of which one or some facets can cross-react, while other facets may be restricted to mono-specific recognition by antibodies to either cholesterol or MA. leads to the inhibition of lysosomal delivery [143,144]. From the perspective of the property of mycolic acids to attract cholesterol and their demonstrated release from trehalose-mycolates at the mycobacterial cell surface, one can predict that MA in the phagosomal membrane would be able to facilitate cholesterol accumulation to ensure TACO retention at the interface between the phagosomal membrane and the mycobacterial cell surface [145].…”

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

“…Quantification of F-and G-actin was carried as previously described (50). In brief, neutrophils (1 3 10 6 /ml) were treated with LTB 4 (100 nM) in the presence and absence of AAT (27.5 mM) or U-75302 (1 mM) for 0, 1, or 5 min.…”

Constitutive Turnover of Phosphorylation at Thr-412 of Human p57/Coronin-1 Regulates the Interaction with Actin

“…The relationship between these phenomena and intracellular parasitism of mycobacteria has been discussed. Recent studies using p57/coronin-1-deficient macrophages showed that lysosomes were efficiently fused with phagosomes containing Mycobacterium bovis BCG (39,40). Thus, p57/coronin-1 is regarded as a molecule blocking lysosomal delivery.…”