Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin
Jayachandran, Rajesh × Sundaramurthy, Varadharajan Combaluzier, Benoit Mueller, Philipp Korf, Hannelie Huygen, Kris Miyazaki, Toru Albrecht, Imke Massner, Jan Pieters, Jean #
Cell vol:130 issue:1 pages:37-50
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 Factindependent processes such as phagocytosis, motility, and membrane ruffling. However, upon mycobacterial infection, coronin 1 was required for activation of the Ca2+- 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 Ca2+ dependent signaling processes in macrophages and reveal a function for calcineurin in the regulation of phagosome- lysosome fusion upon mycobacterial infection.