Sulfated glycosaminoglycans mediate prion-like behavior of p53 aggregates

Naoyuki Iwahashi, Midori Ikezaki, Taro Nishikawa, Norihiro Namba, Takashi Ohgita, Hiroyuki Saito, Yoshito Ihara, Toshinori Shimanouchi, Kazuhiko Ino, Kenji Uchimura, Kazuchika Nishitsuji

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)33225-33234
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number52
DOIs
Publication statusPublished - Dec 2020

Keywords

  • Amyloid
  • Heparan sulfate
  • Ovarian cancer
  • P53
  • Protein aggregates

ASJC Scopus subject areas

  • General

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