2026/05/08 by Edismauro Garcia Freitas Filho, Isabella Zaidan, Daniel L Alzamora-Terrel +12 · 1 voice
Biochemistry, Genetics and Molecular Biology · #ATP Synthase and ATPases Research #Adenosine and Purinergic Signaling #Cellular transport and secretion
paper · pdf · doi:10.1126/sciadv.adz0196
openalex publication_date 2026/05/08 · openalex created_date 2026/05/10 · openalex updated_date 2026/08/01
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.