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Mol Cell. 2019 Mar 6. pii: S1097-2765(19)30100-5. doi: 10.1016/j.molcel.2019.02.010. [Epub ahead of print]

Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy.

Author information

1
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.
2
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
3
Flow and Imaging Cytometry Core Facility, National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892, USA.
4
Department of Neuromuscular Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK; UK Dementia Research Institute at UCL, UCL Queen Square Institute of Neurology, University College London, London WC1E 6BT, UK; Discoveries Centre for Regenerative and Precision Medicine, UCL Campus, University College London, London WC1E 6BT, UK.
5
MRC Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge CB2 0QH, UK; University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
6
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: youler@ninds.nih.gov.

Abstract

Selective autophagy recycles damaged organelles and clears intracellular pathogens to prevent their aberrant accumulation. How ULK1 kinase is targeted and activated during selective autophagic events remains to be elucidated. In this study, we used chemically inducible dimerization (CID) assays in tandem with CRISPR KO lines to systematically analyze the molecular basis of selective autophagosome biogenesis. We demonstrate that ectopic placement of NDP52 on mitochondria or peroxisomes is sufficient to initiate selective autophagy by focally localizing and activating the ULK1 complex. The capability of NDP52 to induce mitophagy is dependent on its interaction with the FIP200/ULK1 complex, which is facilitated by TBK1. Ectopically tethering ULK1 to cargo bypasses the requirement for autophagy receptors and TBK1. Focal activation of ULK1 occurs independently of AMPK and mTOR. Our findings provide a parsimonious model of selective autophagy, which highlights the coordination of ULK1 complex localization by autophagy receptors and TBK1 as principal drivers of targeted autophagosome biogenesis.

KEYWORDS:

ATG13; FIP200; P62; PINK1; Parkin; TAX1BP1; lysosome; mitochondria; mitophagy; optineurin

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