Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages.
Autophagy has been postulated to play role in mammalian host defense against fungal pathogens, although the molecular details remain unclear. Here, we show that primary macrophages deficient in the autophagic factor LC3 demonstrate diminished fungicidal activity but increased cytokine production in response to Candida albicans stimulation. LC3 recruitment to fungal phagosomes requires activation of the fungal pattern receptor dectin-1. LC3 recruitment to the phagosome also requires Syk signaling but is independent of all activity by Toll-like receptors and does not require the presence of the adaptor protein Card9. We further demonstrate that reactive oxygen species generation by NADPH oxidase is required for LC3 recruitment to the fungal phagosome. These observations directly link LC3 to the inflammatory pathway against C. albicans in macrophages.
Department of Medicine, Division of Infectious Diseases Department of Medicine, Harvard Medical School, Boston.
Jenny M
JM
Tam
Department of Medicine, Division of Infectious Diseases Department of Medicine, Harvard Medical School, Boston.
Michael K
MK
Mansour
Department of Medicine, Division of Infectious Diseases.
Nida S
NS
Khan
Department of Medicine, Division of Infectious Diseases.
Michael
M
Seward
Department of Medicine, Division of Infectious Diseases.
Sravanthi
S
Puranam
Icahn School of Medicine at Mt. Sinai, Tisch Cancer Institute.
Antoine
A
Tanne
Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital.
Anna
A
Sokolovska
Gastrointestinal Unit Center for the Study of Inflammatory Bowel Disease Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
Christine E
CE
Becker
Benaroya Research Institute, Seattle, Washington.
Mridu
M
Acharya
National High Magnetic Field Laboratory, Florida State University, Tallahassee.
Michelle A
MA
Baird
Weill Cornell Medical College.
Augustine M K
AM
Choi
National High Magnetic Field Laboratory, Florida State University, Tallahassee.
Michael W
MW
Davidson
Roswell Park Cancer Institute, University of Buffalo School of Medicine, New York.
Brahm H
BH
Segal
Benaroya Research Institute, Seattle, Washington.
Adam
A
Lacy-Hulbert
Benaroya Research Institute, Seattle, Washington.
Lynda M
LM
Stuart
Gastrointestinal Unit Center for the Study of Inflammatory Bowel Disease Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
Ramnik J
RJ
Xavier
Department of Medicine, Division of Infectious Diseases Department of Medicine, Harvard Medical School, Boston.
Jatin M
JM
Vyas
D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology; D002460:Cell Line; D005658:Fungi / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011509:Proteoglycans; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D047071:beta-Glucans / Q000378:metabolism; D000099181:Dectin-1
D053468:CARD Signaling Adaptor Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008869:Microtubule-Associated Proteins; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases; D011509:Proteoglycans; D017382:Reactive Oxygen Species; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha; D047071:beta-Glucans; D000099181:Dectin-1; C513280:Card9 protein, mouse; C480860:Map1lc3b protein, mouse; C010770:polysaccharide-K; C000606897:Syk protein, mouse
Candida albicans; LC3; NADPH oxidase; ROS; autophagy; dectin-1