Melanin targets LC3-associated phagocytosis (LAP): A novel pathogenetic mechanism in fungal disease.

Abstract

Intracellular swelling of conidia of the major human airborne fungal pathogen Aspergillus fumigatus results in surface exposure of immunostimulatory pathogen-associated molecular patterns (PAMPs) and triggers activation of a specialized autophagy pathway called LC3-associated phagocytosis (LAP) to promote fungal killing. We have recently discovered that, apart from PAMPs exposure, cell wall melanin removal during germination of A. fumigatus is a prerequisite for activation of LAP. Importantly, melanin promotes fungal pathogenicity via targeting LAP, as a melanin-deficient A. fumigatus mutant restores its virulence upon conditional inactivation of Atg5 in hematopoietic cells of mice. Mechanistically, fungal cell wall melanin selectively excludes the CYBA/p22phox subunit of NADPH oxidase from the phagosome to inhibit LAP, without interfering with signaling regulating cytokine responses. Notably, inhibition of LAP is a general property of melanin pigments, a finding with broad physiological implications.

• Authors: Georgios Chamilos, Tonia Akoumianaki, Irene Kyrmizi, Axel Brakhage, Anne Beauvais, Jean-Paul Latge
• Journal: Autophagy (Autophagy) Vol. 12 Issue 5 Pg. 888-9 (05 03 2016) ISSN: 1554-8635 [Electronic] United States
• PMID: 27028978 (Publication Type: Journal Article, Review)

Chemical References

• Melanins

Topics

• Animals
• Aspergillus fumigatus
• Humans
• Melanins (metabolism)
• Mycoses (metabolism, microbiology)
• Phagocytosis (physiology)
• Phagosomes (drug effects, metabolism)