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

Mol Cell. 2019 Apr 18;74(2):347-362.e6. doi: 10.1016/j.molcel.2019.02.010. Epub 2019 Mar 7.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics*
  • Autophagy-Related Protein-1 Homolog / genetics*
  • Autophagy-Related Proteins
  • Clustered Regularly Interspaced Short Palindromic Repeats / genetics
  • HeLa Cells
  • Humans
  • Mitochondria / chemistry
  • Mitochondria / genetics
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Nuclear Proteins / genetics*
  • Peroxisomes / chemistry
  • Peroxisomes / genetics
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Multimerization
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / genetics
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics

Substances

  • Autophagy-Related Proteins
  • CALCOCO2 protein, human
  • Multiprotein Complexes
  • Nuclear Proteins
  • RB1CC1 protein, human
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human