Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin.
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.
Jayachandran
Rajesh
R
Biozentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Sundaramurthy
Varadharajan
V
Combaluzier
Benoit
B
Mueller
Philipp
P
Korf
Hannelie
H
Huygen
Kris
K
Miyazaki
Toru
T
Albrecht
Imke
I
Massner
Jan
J
Pieters
Jean
J
D000199:Actins / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D002633:Chemotaxis; D016572:Cyclosporine; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism*; D009161:Mycobacterium / Q000472:pathogenicity / Q000502:physiology*; D009164:Mycobacterium Infections / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology; D010873:Pinocytosis / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016559:Tacrolimus / Q000378:metabolism
D000199:Actins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D008840:Microfilament Proteins; C072061:coronin proteins; D007371:Interferon-gamma; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus