Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages

Jenny M Tam; Michael K Mansour; Nida S Khan; Michael Seward; Sravanthi Puranam; Antoine Tanne; Anna Sokolovska; Christine E Becker; Mridu Acharya; Michelle A Baird; Augustine M K Choi; Michael W Davidson; Brahm H Segal; Adam Lacy-Hulbert; Lynda M Stuart; Ramnik J Xavier; Jatin M Vyas

doi:10.1093/infdis/jiu290

Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages

J Infect Dis. 2014 Dec 1;210(11):1844-54. doi: 10.1093/infdis/jiu290. Epub 2014 May 19.

Authors

Jenny M Tam¹, Michael K Mansour¹, Nida S Khan², Michael Seward², Sravanthi Puranam², Antoine Tanne³, Anna Sokolovska⁴, Christine E Becker⁵, Mridu Acharya⁶, Michelle A Baird⁷, Augustine M K Choi⁸, Michael W Davidson⁷, Brahm H Segal⁹, Adam Lacy-Hulbert⁶, Lynda M Stuart⁶, Ramnik J Xavier⁵, Jatin M Vyas¹

Affiliations

¹ Department of Medicine, Division of Infectious Diseases Department of Medicine, Harvard Medical School, Boston.
² Department of Medicine, Division of Infectious Diseases.
³ Icahn School of Medicine at Mt. Sinai, Tisch Cancer Institute.
⁴ Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital.
⁵ 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.
⁶ Benaroya Research Institute, Seattle, Washington.
⁷ National High Magnetic Field Laboratory, Florida State University, Tallahassee.
⁸ Weill Cornell Medical College.
⁹ Roswell Park Cancer Institute, University of Buffalo School of Medicine, New York.

Abstract

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.

Keywords: Candida albicans; LC3; NADPH oxidase; ROS; autophagy; dectin-1.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
CARD Signaling Adaptor Proteins / metabolism
Candida albicans / immunology
Cell Line
Fungi / immunology*
Interleukin-1beta / biosynthesis
Interleukin-6 / biosynthesis
Intracellular Signaling Peptides and Proteins / metabolism
Lectins, C-Type / genetics*
Lectins, C-Type / metabolism*
Macrophages / immunology
Macrophages / metabolism*
Macrophages / microbiology*
Mice
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism*
Models, Biological
NADPH Oxidases / metabolism
Phagosomes / immunology
Phagosomes / metabolism*
Phagosomes / microbiology
Phosphorylation
Protein-Tyrosine Kinases / metabolism
Proteoglycans
Reactive Oxygen Species / metabolism
Signal Transduction
Syk Kinase
Tumor Necrosis Factor-alpha / biosynthesis
beta-Glucans / metabolism

Substances

CARD Signaling Adaptor Proteins
Card9 protein, mouse
Interleukin-1beta
Interleukin-6
Intracellular Signaling Peptides and Proteins
Lectins, C-Type
Map1lc3b protein, mouse
Microtubule-Associated Proteins
Proteoglycans
Reactive Oxygen Species
Tumor Necrosis Factor-alpha
beta-Glucans
dectin 1
polysaccharide-K
NADPH Oxidases
Protein-Tyrosine Kinases
Syk Kinase
Syk protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding