Expression of the Prion Protein Family Member Shadoo Causes Drug Hypersensitivity That Is Diminished by the Coexpression of the Wild Type Prion Protein

Nyeste, Antal; Bencsura, Petra; Vida, István; Hegyi, Zoltán; Homolya, László; Fodor, Elfrieda; Welker, Ervin

doi:10.1074/jbc.m115.679035

Cited by 5 publications

(19 citation statements)

References 57 publications

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“…By contrast, when expressed in cultured immortalized cells (SH-SY5Y and HEK293) Sho expression caused hypersensitivity to Zeocin or G418, in a dose dependent manner, mimicking the expression of the ΔCR-PrP mutant. This phenotype was also rescued by the co-expression of WT-PrP26. All together, these data indicate that PrP C and Sho may act on the same cellular pathways, via similar mechanisms.…”

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confidence: 51%

“…This domain is also essential for the protective activities of WT-PrP30. In order to examine whether the N-terminal domain of Sho [(RXXX) 8 motif31] is also essential for its drug-sensitizing activity26, we engineered a mutant Sho protein construct lacking amino acids 25 through 61 [ShoΔ(RXXX) 8 ] (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…1). Using an expression system employed previously for the expression of WT-Sho in SH-SY5Y cells, which harbour no detectable amount of endogenous Sho26, we developed cells stably expressing this deletion-mutant. Both WT and mutant Sho correctly localize at the cell surface, being attached to the plasma membrane via glycosylphosphatidylinositol (GPI) anchors (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3e,f). Considering the much lower expression level of ShoΔHD (at a similar level WT-Sho exhibits only reduced activity26), it is likely that ShoΔHD is more effective to induce this phenotype than WT-Sho. While these experiments suggest that the presence of Sho’s HD is not required for conferring drug hypersensitivity, its absence seems to aggravate it.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, in case of Sho the WT protein is the one that itself exerts either protective or toxic activities depending on the experimental paradigms examined252640. However, none of the phenotypes of Sho-expressing cells seen in vitro , protective or toxic, are apparent in vivo .…”

Section: Discussionmentioning

confidence: 99%

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The prion protein family member Shadoo induces spontaneous ionic currents in cultured cells

Nyeste

Stincardini

Bencsura

et al. 2016

Sci Rep

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Some mutant forms of the cellular prion protein (PrPC) carrying artificial deletions or point mutations associated with familial human prion diseases are capable of inducing spontaneous ionic currents across the cell membrane, conferring hypersensitivity to certain antibiotics to a wide range of cultured cells and primary cerebellar granular neurons (CGNs). These effects are abrogated when the wild type (WT) form is co-expressed, suggesting that they might be related to a physiological activity of PrPC. Interestingly, the prion protein family member Shadoo (Sho) makes cells hypersensitive to the same antibiotics as mutant PrP-s, an effect that is diminished by the co-expression of WT-PrP. Here, we report that Sho engages in another mutant PrP-like activity: it spontaneously induces large ionic currents in cultured SH-SY5Y cells, as detected by whole-cell patch clamping. These currents are also decreased by the co-expression of WT-PrP. Furthermore, deletion of the N-terminal (RXXX)8 motif of Sho, mutation of the eight arginine residues of this motif to glutamines, or replacement of the hydrophobic domain by that of PrP, also diminish Sho-induced ionic currents. Our results suggest that the channel activity that is also characteristic to some pathogenic PrP mutants may be linked to a physiological function of Sho.

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mentioning

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The prion protein family member Shadoo induces spontaneous ionic currents in cultured cells

Nyeste

Stincardini

Bencsura

et al. 2016

Sci Rep

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The Prion-like protein Shadoo is involved in mouse embryonic and mammary development and differentiation

Passet

Castille

Makhzami

et al. 2020

Sci Rep

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Shadoo belongs to the prion protein family, an evolutionary conserved and extensively studied family due to the implication of prp in transmissible Spongiform encephalopathies. However, the biological function of these genes remains poorly understood. While Sprn-knockdown experiments suggested an involvement of Shadoo during mouse embryonic development, Sprn-knockout experiments in 129Pas/ C57BL/6J or 129Pas/FVB/NCr mice did not confirm it. In the present study, we analyzed the impact of Sprn gene invalidation in a pure FVB/NJ genetic background, using a zinc finger nuclease approach. The in-depth analysis of the derived knockout transgenic mice revealed a significant increase in embryonic lethality at early post-implantation stages, a growth retardation of young Sprn-knockout pups fed by wild type mice and a lactation defect of Sprn-knockout females. Histological and transcriptional analyses of knockout E7.5 embryos, E14.5 placentas and G7.5 mammary glands revealed specific roles of the Shadoo protein in mouse early embryogenesis, tissue development and differentiation with a potential antagonist action between prp and Shadoo. this study thus highlights the entanglement between the proteins of the prion family.

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The study of the membrane microdomain localization of the prion-family proteins, prion and Shadoo and their interaction with calnexin

Dondapati

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Expression of the Prion Protein Family Member Shadoo Causes Drug Hypersensitivity That Is Diminished by the Coexpression of the Wild Type Prion Protein

Cited by 5 publications

References 57 publications

The prion protein family member Shadoo induces spontaneous ionic currents in cultured cells

The prion protein family member Shadoo induces spontaneous ionic currents in cultured cells

The Prion-like protein Shadoo is involved in mouse embryonic and mammary development and differentiation

The study of the membrane microdomain localization of the prion-family proteins, prion and Shadoo and their interaction with calnexin

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