IndraLab

Statements

SSM4 inhibits KCNH2. 17 / 17
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"Therefore, lanosterol accumulation induced by fluconazole treatment stimulates Doa10 dependent degradation of Erg1."
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"Consistent with previous results showing that drugs targeting specific steps of isoprenoid synthesis largely abolish the Doa10-dependent degradation of Erg1 (Foresti et al., 2013), treatment with terbinafine negated the effect of Δdoa10 on Erg1 protein levels in both the WT and Δget3 strains (Fig. 5, E and F)."
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"Taken together, these data demonstrate that Doa10 dependent degradation of Erg1 is regulated by the levels of sterols, most likely lanosterol."
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"The Doa10 dependent degradation of Erg1 is regulated by lanosterol."
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"Two E3 ubiquitin ligases, Hrd1 and Doa10 are known to mediate the proteasomal degradation of HMG-CoA reductase Hmg2 and squalene epoxidase Erg1 with accumulation of the toxic sterols in cells, but the deubiquitinases (DUBs) involved are unclear."
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"We then asked whether the Doa10 dependent degradation of Erg1 had an effect on sterol homeostasis."
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"Altogether, the data presented so far indicate that sterol dependent degradation of Erg1 by Doa10 is part of a feedback system essential for sterol homeostasis."
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"We have now found that in yeast, high levels of lanosterol also lead to a decrease in flux through the sterol pathway, in this case by the Doa10 dependent degradation of Erg1."
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"In sum, these data show that Are1, Are2 dependent sterol esterification and Doa10 dependent degradation of Erg1 are parallel mechanisms preventing abnormal accumulation of potentially toxic sterol intermediates."
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"Besides the Doa10 dependent degradation of Erg1 in yeast, we show that the Doa10 homologue Teb4 also promotes the degradation of SM in mammalian cells."
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"Moreover, Doa10 dependent degradation of Erg1 requires a single lysine residue that is poorly conserved outside fungi, while proteasomal dependent degradation of SM depends on an N-terminal fragment conserved only in higher animals."
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"We show that Doa10 dependent degradation of Erg1 is regulated by the levels of lanosterol and that, together with sterol esterification, it is essential for preventing the accumulation of toxic sterol intermediates."
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"Thus, the lysine residue at position 311 is essential for Doa10 dependent degradation of Erg1."
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"We then tested whether Doa10 dependent degradation of Erg1 was affected by the levels of cellular sterols."
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"These experiments indicate that sterol depletion specifically affects the Doa10 dependent degradation of Erg1 but not other Doa10 substrates, such as misfolded proteins."
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"The Doa10 mediated degradation of Erg1 is stimulated by lanosterol, which is a downstream product of this pathway."
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"The degradation of Erg1 by Doa10 does not involve proteins that are involved in degrading misfolded proteins but does involve proteins that are involved in ERAD, specifically Cdc48, which is an ATPase involved in extruding proteins from the ER membrane."
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