Heparan sulfate is a clearance receptor for aberrant extracellular proteins

J Cell Biol. 2020 Mar 2;219(3):e201911126. doi: 10.1083/jcb.201911126.


The accumulation of aberrant proteins leads to various neurodegenerative disorders. Mammalian cells contain several intracellular protein degradation systems, including autophagy and proteasomal systems, that selectively remove aberrant intracellular proteins. Although mammals contain not only intracellular but also extracellular proteins, the mechanism underlying the quality control of aberrant extracellular proteins is poorly understood. Here, using a novel quantitative fluorescence assay and genome-wide CRISPR screening, we identified the receptor-mediated degradation pathway by which misfolded extracellular proteins are selectively captured by the extracellular chaperone Clusterin and undergo endocytosis via the cell surface heparan sulfate (HS) receptor. Biochemical analyses revealed that positively charged residues on Clusterin electrostatically interact with negatively charged HS. Furthermore, the Clusterin-HS pathway facilitates the degradation of amyloid β peptide and diverse leaked cytosolic proteins in extracellular space. Our results identify a novel protein quality control system for preserving extracellular proteostasis and highlight its role in preventing diseases associated with aberrant extracellular proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Cell Membrane / metabolism*
  • Clusterin / genetics
  • Clusterin / metabolism*
  • Endocytosis*
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Heparitin Sulfate / metabolism*
  • Humans
  • Intrinsically Disordered Proteins / chemistry
  • Intrinsically Disordered Proteins / metabolism*
  • Lysosomes / metabolism
  • Protein Folding
  • Proteolysis
  • Proteostasis
  • Surface Properties
  • Time Factors


  • Amyloid beta-Peptides
  • CLU protein, human
  • Clusterin
  • Intrinsically Disordered Proteins
  • Heparitin Sulfate