Yeast Sec14‐like lipid transfer proteins Pdr16 and Pdr17 bind and transfer the ergosterol precursor lanosterol in addition to phosphatidylinositol

Šťastný, Dominik; Petriskova, Livia; Tahotná, Dana; Bauer, Jacob; Pokorná, Lucia; Holic̆, Roman; Valachovič, Martin; Pevala, Vladimír; Cockcroft, Shamshad; Griač, Peter

doi:10.1002/1873-3468.14558

Cited by 10 publications

(4 citation statements)

References 48 publications

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“…Therefore, it would be important to investigate whether or not the functions of Pdr16 and Pdr17 in sterol metabolism and transport are involved in acquisition of AbA resistance under impaired biosynthesis of ergosterol. However, it should be noted that in vitro transfer activity of sterol and contribution to in vivo sterol metabolism are not significantly different between Pdr16 and Pdr17 43 , whereas, in the resistance to AbA in ERG6 -deleted cells, the contribution of Pdr16 is much higher than that of Pdr17 (Figs. 4 A and 5 ).…”

Section: Discussionmentioning

confidence: 88%

“…The deletion of PDR16 and/or PDR17 causes a reduction in the ergosterol level and accumulation of its synthetic intermediates 42 . Furthermore, very recently, it was reported that, in an in vitro assay, Pdr16 and Pdr17 facilitate transfer of lanosterol, an ergosterol precursor, between membranes 43 . Therefore, it would be important to investigate whether or not the functions of Pdr16 and Pdr17 in sterol metabolism and transport are involved in acquisition of AbA resistance under impaired biosynthesis of ergosterol.…”

Section: Discussionmentioning

confidence: 99%

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Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner

Fukuda

Kono

Ishibashi

et al. 2023

Sci Rep

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Complex sphingolipids and sterols are coordinately involved in various cellular functions, e.g. the formation of lipid microdomains. Here we found that budding yeast exhibits resistance to an antifungal drug, aureobasidin A (AbA), an inhibitor of Aur1 catalyzing the synthesis of inositolphosphorylceramide, under impaired biosynthesis of ergosterol, which includes deletion of ERG6, ERG2, or ERG5 involved in the final stages of the ergosterol biosynthesis pathway or miconazole; however, these defects of ergosterol biosynthesis did not confer resistance against repression of expression of AUR1 by a tetracycline-regulatable promoter. The deletion of ERG6, which confers strong resistance to AbA, results in suppression of a reduction in complex sphingolipids and accumulation of ceramides on AbA treatment, indicating that the deletion reduces the effectiveness of AbA against in vivo Aur1 activity. Previously, we reported that a similar effect to AbA sensitivity was observed when PDR16 or PDR17 was overexpressed. It was found that the effect of the impaired biosynthesis of ergosterol on the AbA sensitivity is completely abolished on deletion of PDR16. In addition, an increase in the expression level of Pdr16 was observed on the deletion of ERG6. These results suggested that abnormal ergosterol biosynthesis confers resistance to AbA in a PDR16-dependent manner, implying a novel functional relationship between complex sphingolipids and ergosterol.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Impaired biosynthesis of ergosterol confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in a PDR16-dependent manner

Fukuda

Kono

Ishibashi

et al. 2023

Sci Rep

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“…In addition, a genome-wide approach for studying drug resistance pathways, identified overexpression of phosphatidylinositol transfer protein (PDR16) confers resistance to AmB in S. cerevisiae and C. albicans [205,206]. The resistance provided by PDR16 overexpression may be connected to an alteration in membrane permeability and lipid composition as PDR16 affects the distribution of membrane ergosterols [207,208]. Similar to this, a different study found that a non-essential gene plasma membrane proteolipid 3 (PMP3) in S. cerevisiae, modifies AmB resistance [209].…”

Section: Amb: Resistance Mechanismsmentioning

confidence: 99%

Antifungal drug resistance in Candida: a special emphasis on amphotericin B

Ahmady,

Gothwal,

Mukkoli

et al. 2024

APMIS

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Invasive fungal infections in humans caused by several Candida species, increased considerably in immunocompromised or critically ill patients, resulting in substantial morbidity and mortality. Candida albicans is the most prevalent species, although the frequency of these organisms varies greatly according to geographic region. Infections with C. albicans and non‐albicans Candida species have become more common, especially in the past 20 years, as a result of aging, immunosuppressive medication use, endocrine disorders, malnourishment, extended use of medical equipment, and an increase in immunogenic diseases. Despite C. albicans being the species most frequently associated with human infections, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei also have been identified. Several antifungal drugs with different modes of action are approved for use in clinical settings to treat fungal infections. However, due to the common eukaryotic structure of humans and fungi, only a limited number of antifungal drugs are available for therapeutic use. Furthermore, drug resistance in Candida species has emerged as a result of the growing use of currently available antifungal drugs against fungal infections. Amphotericin B (AmB), a polyene class of antifungal drugs, is mainly used for the treatment of serious systemic fungal infections. AmB interacts with fungal plasma membrane ergosterol, triggering cellular ion leakage via pore formation, or extracting the ergosterol from the plasma membrane inducing cellular death. AmB resistance is primarily caused by changes in the content or structure of ergosterol. This review summarizes the antifungal drug resistance exhibited by Candida species, with a special focus on AmB.

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“…It is clearly recruited by Ldo45 to LDs [13], but its specific role in micro-lipophagy remains unclear. Of note, Pdr16 is a Sec14 homolog with predicted phosphoinositol lipid transport activity that influences LD homeostasis [14], but more recent reports indicate it may also transport ergosterol precursors in addition to phospholipids [15]. A tempting model is that Pdr16 promotes the transport of lipids into or out of NVJ-associated LDs, and this influences LD and vacuole-lipid composition for micro-lipophagy progression, but this requires more study.…”

Section: Outlook and Future Directionsmentioning

confidence: 99%