RAB5c orchestrates LC3-associated phagocytosis to promote microbicidal function of macrophages

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Abstract
Noncanonical conjugation of ATG8 proteins, including LC3, to single membranes implicates the autophagy machinery in cell functions unrelated to metabolic stress. One such pathway is LC3-associated phagocytosis (LAP), which aids in phagosome maturation and subsequent signaling upon cargo uptake mediated by certain innate immunity-associated receptors. Here, we show that a specific isoform of RAB5 GTPases, the molecular switches controlling early endosome traffic, is necessary for LAP. We demonstrate that RAB5c regulates phagosome recruitment and function of complexes required for phosphatidylinositol 3-phosphate [PI(3)P] and reactive oxygen species (ROS) generation by macrophages. RAB5c facilitates phagosome translocation of the V-ATPase transmembrane core, which is needed for ATG16L1 binding and consequent LC3 conjugation. RAB5c depletion impaired macrophage elimination of the fungal pathogen Aspergillus fumigatus and disruption of the V-ATPase–ATG16L1 axis increased susceptibility in vivo. Thus, early endosome-to-phagosome trafficking can be selectively engaged to promote pathogen elimination by directing phagosomal maturation toward LAP.
Funding Information
  • National Institute of Allergy and Infectious Diseases (R01AI153356)
  • Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0433)
  • Biotechnology and Biological Sciences Research Council (BBS/E/000C0535)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88887.507253/2020-00)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (434538/2018-3)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (309943/2022-1)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (301058/2019-9)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/25559-4)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2019/26040-5)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2013/08216-2)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2022/08177-6)
  • Journal of Cell Science Travelling Fellowship (JCSTF25011784)
  • National Institute of Science and Technology (405934/2022-0)

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