Integrated proteomics identifies p62-dependent selective autophagy of the supramolecular vault complex

Dev Cell. 2023 Jul 10;58(13):1189-1205.e11. doi: 10.1016/j.devcel.2023.04.015. Epub 2023 May 15.


In addition to membranous organelles, autophagy selectively degrades biomolecular condensates, in particular p62/SQSTM1 bodies, to prevent diseases including cancer. Evidence is growing regarding the mechanisms by which autophagy degrades p62 bodies, but little is known about their constituents. Here, we established a fluorescence-activated-particle-sorting-based purification method for p62 bodies using human cell lines and determined their constituents by mass spectrometry. Combined with mass spectrometry of selective-autophagy-defective mouse tissues, we identified vault, a large supramolecular complex, as a cargo within p62 bodies. Mechanistically, major vault protein directly interacts with NBR1, a p62-interacting protein, to recruit vault into p62 bodies for efficient degradation. This process, named vault-phagy, regulates homeostatic vault levels in vivo, and its impairment may be associated with non-alcoholic-steatohepatitis-derived hepatocellular carcinoma. Our study provides an approach to identifying phase-separation-mediated selective autophagy cargoes, expanding our understanding of the role of phase separation in proteostasis.

Keywords: Mallory-Denk body; NBR1; fluorescence-activated particle sorting; hepatocellular carcinoma; liquid-liquid phase separation; non-alcoholic steatohepatitis; p62/SQSTM1; selective autophagy; vault; vault-phagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Humans
  • Liver Neoplasms*
  • Mice
  • Organelles / metabolism
  • Proteomics*
  • Sequestosome-1 Protein / metabolism


  • Sequestosome-1 Protein