Sulfated glycosaminoglycans mediate prion-like behavior of p53 aggregates

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.

Phase separation of p53 precedes aggregation and is affected by oncogenic mutations and ligands

“…Recently, sulfated glycosaminoglycans (GAGs) were shown to mediate the prion-like aggregation behavior of p53 by specifically acting on the GAG-dependent cellular uptake of p53 aggregates. 62 Low molecular weight heparin was proposed to modulate mammalian PrP prion conversion. 63 The anticancer effect of heparin may be related to both inhibition of the prion effect and modulation of the phase transition.…”

SULF2 Is a Prognostic Biomarker and Correlated with Tumor Associated Macrophages in Gastric Cancer

“…SULF2 expression, which was induced by p53, then promoted IL-6 expression by stabilizing β-catenin, followed by stimulation of the STAT3/Bcl-XL pathway 33 . Though SULF2 was con rmed to be a direct transcription target of p53 34 , SULF2 might also regulate prion-like behavior of p53 through remodeling HSGAG Sdomains in cancer 35 . This interaction between SULF2 and p53 may promote the progression of GC.…”

Protein of a thousand faces: The tumor-suppressive and oncogenic responses of p53

“…Our results reveal that p53-DBD and p53-DBD-R248Q are prone to aggregate in vitro as amyloid fibrils ( Ishimaru et al, 2003 ). Interestingly, the mutant shows a prion-like behavior, accelerating wild-type p53-DBD aggregation ( Ano Bom et al, 2012 ; Ghosh et al, 2017 ; Iwahashi et al, 2020 ; Navalkar et al, 2021 ; Park et al, 2021 ). The prionoid characteristics include pathological misfolding, template conversion, aggregation, and self-propagation.…”