Sulfated glycosaminoglycans mediate prion-like behavior of p53 aggregates

Proc Natl Acad Sci U S A. 2020 Dec 29;117(52):33225-33234. doi: 10.1073/pnas.2009931117. Epub 2020 Dec 14.

Abstract

Sulfated glycosaminoglycans (GAGs) such as heparan sulfate (HS) are heteropolysaccharides implicated in the pathology of protein aggregation diseases including localized and systemic forms of amyloidosis. Among subdomains of sulfated GAGs, highly sulfated domains of HS, called HS S-domains, have been highlighted as being critical for HS function in amyloidoses. Recent studies suggest that the tumor suppressor p53 aggregates to form amyloid fibrils and propagates in a prion-like manner; however, molecules and mechanisms that are involved in the prion-like behavior of p53 aggregates have not been addressed. Here, we identified sulfated GAGs as molecules that mediate prion-like behavior of p53 aggregates. Sulfated GAGs at the cell surface were required for cellular uptake of recombinant and cancer cell-derived p53 aggregates and extracellular release of p53 from cancer cells. We further showed that HS S-domains accumulated within p53 deposits in human ovarian cancer tissues, and enzymatic remodeling of HS S-domains by Sulf-2 extracellular sulfatase down-regulated cellular uptake of p53 aggregates. Finally, sulfated GAG-dependent cellular uptake of p53 aggregates was critical for subsequent extracellular release of the aggregates and gain of oncogenic function in recipient cells. Our work provides a mechanism of prion-like behavior of p53 aggregates and will shed light on sulfated GAGs as a common mediator of prions.

Keywords: amyloid; heparan sulfate; ovarian cancer; p53; protein aggregates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cell Membrane / metabolism
  • Cricetulus
  • Endocytosis
  • Female
  • Glycosaminoglycans / metabolism*
  • Heparitin Sulfate / metabolism
  • Humans
  • Mutation / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Prions / metabolism*
  • Protein Aggregates*
  • Recombinant Proteins / metabolism
  • Sulfates / metabolism*
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Glycosaminoglycans
  • Prions
  • Protein Aggregates
  • Recombinant Proteins
  • Sulfates
  • Tumor Suppressor Protein p53
  • Heparitin Sulfate