Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins

Jennifer Martinez, R. K.Subbarao Malireddi, Qun Lu, Larissa Dias Cunha, Stephane Pelletier, Sebastien Gingras, Robert Orchard, Jun Lin Guan, Haiyan Tan, Junmin Peng, Thirumala Devi Kanneganti, Herbert W. Virgin, Douglas R. Green

Research output: Contribution to journalArticle

323 Scopus citations

Abstract

LC3-associated phagocytosis (LAP) is a process wherein elements of autophagy conjugate LC3 to phagosomal membranes. We characterize the molecular requirements for LAP, and identify Rubicon as being required for LAP but not autophagy. Rubicon is recruited to LAPosomes and is required for the activity of a Class III PI(3)K complex containing UVRAG but lacking ATG14 and Ambra1. This allows for the sustained localization of PtdIns(3)P, which is critical for recruitment of downstream autophagic proteins and stabilization of the NOX2 complex to produce reactive oxygen species. Both PtdIns(3)P and reactive oxygen species are required for conjugation of LC3 to LAPosomes and subsequent association with LAMP1 + lysosomes. LAP is induced by engulfment of Aspergillus fumigatus, a fungal pathogen that commonly afflicts immunocompromised hosts, and is required for its optimal clearance in vivo. Therefore, we have identified molecules that distinguish LAP from canonical autophagy, thereby elucidating the importance of LAP in response to A. fumigatus infection.

Original languageEnglish (US)
Pages (from-to)893-906
Number of pages14
JournalNature cell biology
Volume17
Issue number7
DOIs
StatePublished - Jul 2 2015

ASJC Scopus subject areas

  • Cell Biology

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    Martinez, J., Malireddi, R. K. S., Lu, Q., Cunha, L. D., Pelletier, S., Gingras, S., Orchard, R., Guan, J. L., Tan, H., Peng, J., Kanneganti, T. D., Virgin, H. W., & Green, D. R. (2015). Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nature cell biology, 17(7), 893-906. https://doi.org/10.1038/ncb3192