ULK1 phosphorylation of striatin activates protein phosphatase 2A and autophagy

Cell Rep. 2021 Sep 28;36(13):109762. doi: 10.1016/j.celrep.2021.109762.

Abstract

The evolutionarily conserved ULK1 kinase complex acts as gatekeeper of canonical autophagy and regulates induction of autophagosome biogenesis. To better understand control of ULK1 and analyze whether ULK1 has broader functions that are also linked to the later steps of autophagy, we perform comprehensive phosphoproteomic analyses. Combining in vivo with in vitro data, we identify numerous direct ULK1 target sites within autophagy-relevant proteins that are critical for autophagosome maturation and turnover. In addition, we highlight an intimate crosstalk between ULK1 and several phosphatase complexes. ULK1 is not only a PP2A target but also directly phosphorylates the regulatory PP2A subunit striatin, activating PP2A and serving as positive feedback to promote autophagy-dependent protein turnover. Thus, ULK1 and phosphatase activities are tightly coordinated to robustly regulate protein degradation by autophagy.

Keywords: PP2A; STRIPAK; STRN; autophagy; in vitro kinase assay; kinase; mass spectrometry; phosphatase; phosphoproteomics; signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagosomes / metabolism
  • Autophagy / physiology*
  • Autophagy-Related Protein-1 Homolog / metabolism*
  • Autophagy-Related Proteins / metabolism
  • Calmodulin-Binding Proteins / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Phosphorylation
  • Protein Phosphatase 2 / metabolism*
  • Protein Processing, Post-Translational / physiology

Substances

  • Autophagy-Related Proteins
  • Calmodulin-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • STRN protein, human
  • Autophagy-Related Protein-1 Homolog
  • ULK1 protein, human
  • Protein Phosphatase 2