title: 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.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Jayachandran
authors.forename: Varadharajan
authors.initials: V
authors.lastname: Sundaramurthy
authors.forename: Benoit
authors.initials: B
authors.lastname: Combaluzier
authors.forename: Philipp
authors.initials: P
authors.lastname: Mueller
authors.forename: Hannelie
authors.initials: H
authors.lastname: Korf
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Imke
authors.initials: I
authors.lastname: Albrecht
authors.forename: Jan
authors.initials: J
authors.lastname: Massner
authors.forename: Jean
authors.initials: J
authors.lastname: Pieters
mesh_terms: 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
chemical_list: D000199:Actins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D008840:Microfilament Proteins; C072061:coronin proteins; D007371:Interferon-gamma; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus