Noncanonical autophagy is a target of fungal cell wall melanin

Ref ID: 19586

Author:

T Akoumianaki1*, I Kyrmizi1, M Gresnigt2, G Samonis1, DP Kontoyiannis5, MG Netea2,
FL van de Veerdonk2, AA Brakhage4, JP Latgé3, G Chamilos1

Author address:

1Department of Medicine, University of Crete, Heraklion, Greece
2Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
3Unite 180 des Aspergillus, Institut Pasteur, Paris, France
4Department of Molecular and

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Activation of noncanonical autophagy via the engagement of signaling receptors regulates phagosome
maturation and participates in many physiologic responses, including the killing of bacterial and
fungal pathogens. In Aspergillus fumigatus, the predominant airborne fungal pathogen in humans,
dormant spores are immunologically inert because cell wall immunostimulatory molecules
are covered by a layer of hydrophobic rodlet protein RodA and melanin. Upon germination of
A. fumigatus spores, surface exposure of β -glucan triggers autophagy protein recruitment to the
phagosome and facilitates fungal killing. Whether masking of immunostimulatory molecules is the
sole mechanism of the fungus to evade noncanonical autophagy is currently unknown.
Methods:
We investigated the mechanism of autophagy protein recruitment in the phagosome of A. fumigatus
mutants lacking RodA and/or cell wall melanin by immunostaining and western blot analysis. The
contribution of autophagy in killing of A. fumigatus was evaluated in Atg5 defective macrophages.
Results:
Surprisingly, we found that genetically enforced β -glucan surface exposure in dormant spores
of A. fumigatus upon the removal of RodA layer (916;rodA mutant) failed to activate noncanonical
autophagy. In contrast, lack of cell wall melanin in dormant spores of 916;rodA/alb1 and 916;pksP mutants
was necessary and sufficient to trigger robust LC3+ phagosome formation via β -glucan-dependent
activation of NADPH oxidase. Cell wall melanin in the absence of RodA or upon exogenous melanin
complementation in 916;rodA/alb1 spores did not interfere with β -glucan-mediated signaling regulating
cytokine release, but selectively blocked noncanonical autophagy by inhibiting NADPH oxidase.
Importantly, melanin-defective A. fumigatus mutants displayed increased susceptibility to killing
that was dependent on noncanonical autophagy as it was restored in Atg5 defective macrophages.
Conclusion:
Collectively, we identified noncanonical autophagy as a molecular target of fungal cell wall melanin.
NOTE: THIS ABSTRACT HAS BEEN SELECTED FOR ORAL PRESENTATION.

Abstract Number: 111

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

Conference abstracts, posters & presentations

Showing 10 posts of 17325 posts found.

  • Title

    Author

    Year

    Number

    Poster