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.

• Authors: Rajesh Jayachandran, Varadharajan Sundaramurthy, Benoit Combaluzier, Philipp Mueller, Hannelie Korf, Kris Huygen, Toru Miyazaki, Imke Albrecht, Jan Massner, Jean Pieters
• Journal: Cell (Cell) Vol. 130 Issue 1 Pg. 37-50 (Jul 13 2007) ISSN: 0092-8674 [Print] United States
• PMID: 17632055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Enzyme Inhibitors
• Immunosuppressive Agents
• Microfilament Proteins
• coronin proteins
• Interferon-gamma
• Cyclosporine
• Calcineurin
• Tacrolimus

Topics

• Actins (metabolism)
• Animals
• Calcineurin (metabolism)
• Cells, Cultured
• Chemotaxis
• Cyclosporine
• Cytoskeleton (metabolism)
• Enzyme Activation
• Enzyme Inhibitors (metabolism)
• Immunosuppressive Agents (metabolism)
• Interferon-gamma (metabolism)
• Lysosomes (metabolism)
• Macrophages (cytology, metabolism, microbiology)
• Male
• Mice
• Mice, Inbred DBA
• Mice, Knockout
• Microfilament Proteins (metabolism)
• Mycobacterium (pathogenicity, physiology)
• Mycobacterium Infections (metabolism)
• Phagocytosis (physiology)
• Phagosomes (metabolism, microbiology)
• Pinocytosis (physiology)
• Signal Transduction (physiology)
• Tacrolimus (metabolism)