The Cargo Receptor NDP52 Initiates Selective Autophagy by Recruiting the ULK Complex to Cytosol-Invading Bacteria

• Published in: Molecular cell Vol. 74; no. 2; pp. 320 - 329.e6
• Main Authors: Ravenhill, Benjamin J., Boyle, Keith B., von Muhlinen, Natalia, Ellison, Cara J., Masson, Glenn R., Otten, Elsje G., Foeglein, Agnes, Williams, Roger, Randow, Felix
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.04.2019; Cell Press
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - genetics; Autophagy - genetics; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Proteins; Binding Sites - genetics; cargo receptor; Cytoplasm - microbiology; Cytosol - microbiology; FIP200; galectin-8; Humans; Multiprotein Complexes - chemistry; Multiprotein Complexes - genetics; NDP52; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Point Mutation - genetics; Protein Binding - genetics; Protein-Serine-Threonine Kinases - genetics; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Salmonella enterica; Salmonella typhimurium - genetics; Salmonella typhimurium - pathogenicity; selective autophagy; TBK1; ULK; xenophagy; xenophagy; Salmonella enterica; TBK1; ULK; galectin-8; selective autophagy; FIP200; NDP52; cargo receptor
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.01.041

Xenophagy, a selective autophagy pathway that protects the cytosol against bacterial invasion, relies on cargo receptors that juxtapose bacteria and phagophore membranes. Whether phagophores are recruited from a constitutive pool or are generated de novo at prospective cargo remains unknown. Phagophore formation in situ would require recruitment of the upstream autophagy machinery to prospective cargo. Here, we show that, essential for anti-bacterial autophagy, the cargo receptor NDP52 forms a trimeric complex with FIP200 and SINTBAD/NAP1, which are subunits of the autophagy-initiating ULK and the TBK1 kinase complex, respectively. FIP200 and SINTBAD/NAP1 are each recruited independently to bacteria via NDP52, as revealed by selective point mutations in their respective binding sites, but only in their combined presence does xenophagy proceed. Such recruitment of the upstream autophagy machinery by NDP52 reveals how detection of cargo-associated “eat me” signals, induction of autophagy, and juxtaposition of cargo and phagophores are integrated in higher eukaryotes. [Display omitted] •NDP52 recruits upstream autophagy machinery to damaged Salmonella-containing vacuoles•NDP52 trimerizes with the ULK subunit FIP200 and the TBK1 adaptor SINTBAD•NDP52-dependent recruitment of FIP200-ULK and SINTBAD-TBK1 required for xenophagy•Recruitment of ULK and TBK1 complexes promotes phagophore formation in situ Selective autophagy defends the cytosol against invasive bacteria. In this study, Ravenhill et al. report that the cargo receptor NDP52 recruits the upstream autophagy machinery to cytosolic bacteria by trimerizing with FIP200 and SINTBAD, subunits of the ULK and TBK1 complexes, respectively.