Gene

Biogenesis

Kinase

Cell biology

Mitochondrial biogenesis

Mitophagy

Biology

Apoptosis

Autophagy

Signal transduction

Biochemistry

ULK1

Protein kinase A

PINK1

Autophagosome

AMPK

BAG3

Mitochondrion

PI3K/AKT/mTOR pathway

Molecular Cell

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.

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