Autophagy receptor NDP52 regulates pathogen-containing autophagosome maturation

Xenophagy, an essential anti-microbial cell-autonomous mechanism, relies on the ability of the autophagic process to selectively entrap intracellular pathogens within autophagosomes to degrade them in autolysosomes. This selective targeting is carried out by specialized autophagy receptors, such as NDP52, but it is unknown whether the fusion of pathogen-containing autophagosomes with lysosomes is also regulated by pathogen-specific cellular factors. Here, we show that NDP52 also promotes the maturation of autophagosomes via its interaction with LC3A, LC3B, and/or GABARAPL2 through a distinct LC3-interacting region, and with MYOSIN VI. During Salmonella Typhimurium infection, the regulatory function of NDP52 in autophagosome maturation is complementary but independent of its function in pathogen targeting to autophagosomes, which relies on the interaction with LC3C. Thus, complete xenophagy is selectively regulated by a single autophagy receptor, which initially orchestrates bacteria targeting to autophagosomes and subsequently ensures pathogen degradation by regulating pathogen-containing autophagosome maturation.