Abstract
Autophagy is a finely orchestrated cellular catabolic process that requires multiple autophagy-related gene products (ATG proteins). The ULK1 complex functions to integrate upstream signals to downstream ATG proteins through an unknown mechanism. Here we have identified an interaction between mammalian FIP200 and ATG16L1, essential components of the ULK1 and ATG5 complexes, respectively. Further analyses show this is a direct interaction mediated by a short domain of ATG16L1 that we term the FIP200-binding domain (FBD). The FBD is not required for ATG16L1 self-dimerization or interaction with ATG5. Notably, an FBD-deleted ATG16L1 mutant is defective in mediating amino acid starvation–induced autophagy, which requires the ULK1 complex. However, this mutant retains its function in supporting glucose deprivation–induced autophagy, a ULK1 complex–independent process. This study therefore identifies a previously uncharacterized interaction between the ULK1 and ATG5 complexes that can distinguish ULK1-dependent and -independent autophagy processes.
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Change history
13 January 2013
In the version of this article initially published online, grant number RO1CA166413 was not acknowledged. The error has been corrected for the print, PDF and HTML versions of this article.
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Acknowledgements
We thank S. Akira (Osaka University) for Atg16l1−/− MEFs, M. Komatsu (Tokyo Metropolitan Institute of Medical Science) for Atg3−/− MEFs, N. Mizushima (Tokyo Medical and Dental University) for Atg5−/− MEFs, C. Thompson (Memorial Sloan Kettering Cancer Center, MSKCC) for ULK1 and ULK2 double-knockout MEFs, F. Giancotti (MSKCC) for β-integrin–specific antibody and H. Erdjument-Bromage (MSKCC) for mass spectrometric analyses. We thank members of the X.J. laboratory for critical reading of the manuscript and discussion. This work was supported in part by US National Institutes of Health (NIH) grants U54CA137788, R01CA113890 and R01CA166413 (to X.J.); US National Cancer Institute grant R01CA154649, the Benjamin Friedman Research Fund and the Louis V. Gerstner, Jr. Young Investigators Fund (to M.O.); and NIH fellowship 1F32CA162691 (to N.G.).
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N.G. and X.J. designed the study and wrote the paper; N.G. and O.F. performed the experiments; N.G., O.F., M.O. and X.J. analyzed the data.
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Gammoh, N., Florey, O., Overholtzer, M. et al. Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex–dependent and –independent autophagy. Nat Struct Mol Biol 20, 144–149 (2013). https://doi.org/10.1038/nsmb.2475
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DOI: https://doi.org/10.1038/nsmb.2475
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