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

Benjamin J Ravenhill,Keith B Boyle,Natalia Von Muhlinen,Cara J Ellison,Glenn R Masson,Elsje G Otten,Agnes Foeglein,Roger Williams,Felix Randow

doi:10.1016/j.molcel.2019.01.041

Benjamin J Ravenhill, Keith B Boyle + Show 7 more

Open Access

https://doi.org/10.1016/j.molcel.2019.01.041

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Abstract

SummaryXenophagy, 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.

Highlights

Macroautophagy, a major degradative pathway in eukaryotic cells, is essential for cellular homeostasis
We show that the cargo receptor NDP52 forms a trimeric complex with FIP200 and SINTBAD/NAP1, subunits of the autophagy-initiating ULK and the TBK1 kinase complex, respectively, which explains how galectin-8-positive membrane fragments, via NDP52, recruit the upstream autophagy machinery to S
These data reveal the existence of a trimeric protein complex, in which the cargo receptor NDP52 binds simultaneously to the ULK complex subunit FIP200 and the TBK1 adaptors SINTBAD/NAP1 and potentially recruits two kinase complexes essential for anti-bacterial autophagy into the vicinity of cytosol-invading bacteria

Summary

Graphical Abstract

Natalia von Muhlinen, ..., Agnes Foeglein, Roger Williams, Felix Randow. Selective autophagy defends the cytosol against invasive bacteria. 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. 2019, Molecular Cell 74, 320–329 April 18, 2019 a 2019 MRC Laboratory of Molecular Biology.

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