ATG8-Binding UIM Proteins Define a New Class of Autophagy Adaptors and Receptors

Cell. 2019 Apr 18;177(3):766-781.e24. doi: 10.1016/j.cell.2019.02.009. Epub 2019 Apr 4.

Abstract

During autophagy, vesicle dynamics and cargo recruitment are driven by numerous adaptors and receptors that become tethered to the phagophore through interactions with lipidated ATG8/LC3 decorating the expanding membrane. Most currently described ATG8-binding proteins exploit a well-defined ATG8-interacting motif (AIM, or LC3-interacting region [LIR]) that contacts a hydrophobic patch on ATG8 known as the LIR/AIM docking site (LDS). Here we describe a new class of ATG8 interactors that exploit ubiquitin-interacting motif (UIM)-like sequences for high-affinity binding to an alternative ATG8 interaction site. Assays with candidate UIM-containing proteins together with unbiased screens identified a large collection of UIM-based ATG8 interactors in plants, yeast, and humans. Analysis of a subset also harboring ubiquitin regulatory X (UBX) domains revealed a role for UIM-directed autophagy in clearing non-functional CDC48/p97 complexes, including some impaired in human disease. With this new class of adaptors and receptors, we greatly extend the reach of selective autophagy and identify new factors regulating autophagic vesicle dynamics.

Keywords: AIM; ATG8; ATG8-interacting motif; Arabidopsis; CDC48/p97; LC3-interacting region; LDS; LIR; LIR/AIM-docking site; UDS; UIM; UIM-docking site; autophagy; ubiquitin-interacting motif; yeast.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Arabidopsis / metabolism
  • Arabidopsis Proteins / chemistry
  • Arabidopsis Proteins / metabolism
  • Autophagy*
  • Autophagy-Related Protein 8 Family / chemistry
  • Autophagy-Related Protein 8 Family / metabolism*
  • Binding Sites
  • Humans
  • Microtubule-Associated Proteins / chemistry
  • Microtubule-Associated Proteins / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Tertiary
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sequence Alignment

Substances

  • Arabidopsis Proteins
  • Autophagy-Related Protein 8 Family
  • Microtubule-Associated Proteins
  • PSMD4 protein, human
  • RNA-Binding Proteins
  • Saccharomyces cerevisiae Proteins