Plasma Membrane Proteolipid 3 Protein Modulates Amphotericin B Resistance through Sphingolipid Biosynthetic Pathway.

Vinay K Bari,Md Alfatah,Sushma Sharma,K Ganesan,Alok K Mondal

doi:10.1038/srep09685

Vinay K Bari, Md Alfatah + Show 3 more

Open Access

https://doi.org/10.1038/srep09685

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Abstract

Invasive opportunistic fungal infections of humans are common among those suffering from impaired immunity, and are difficult to treat resulting in high mortality. Amphotericin B (AmB) is one of the few antifungals available to treat such infections. The AmB resistance mechanisms reported so far mainly involve decrease in ergosterol content or alterations in cell wall. In contrast, depletion of sphingolipids sensitizes cells to AmB. Recently, overexpression of PMP3 gene, encoding plasma membrane proteolipid 3 protein, was shown to increase and its deletion to decrease, AmB resistance. Here we have explored the mechanistic basis of PMP3 effect on AmB resistance. It was found that ergosterol content and cell wall integrity are not related to modulation of AmB resistance by PMP3. A few prominent phenotypes of PMP3 delete strain, namely, defective actin polarity, impaired salt tolerance, and reduced rate of endocytosis are also not related to its AmB-sensitivity. However, PMP3 overexpression mediated increase in AmB resistance requires a functional sphingolipid pathway. Moreover, AmB sensitivity of strains deleted in PMP3 can be suppressed by the addition of phytosphingosine, a sphingolipid pathway intermediate, confirming the importance of this pathway in modulation of AmB resistance by PMP3.

Highlights

Invasive opportunistic fungal infections of humans are common among those suffering from impaired immunity, and are difficult to treat resulting in high mortality
We have recently shown that sphingolipids modulate Amphotericin B (AmB) resistance[12]
The S. cerevisiae PMP3 gene was isolated from a multicopy overexpression library as conferring higher resistance to AmB

Summary

Modulates Amphotericin B Resistance through Sphingolipid Biosynthetic

CSIR-Institute of Microbial Technology, Sector 39-A, Chandigarh – 160036, India. Invasive opportunistic fungal infections of humans are common among those suffering from impaired immunity, and are difficult to treat resulting in high mortality. The AmB resistance mechanisms reported so far mainly involve decrease in ergosterol content or alterations in cell wall. Overexpression of PMP3 gene, encoding plasma membrane proteolipid 3 protein, was shown to increase and its deletion to decrease, AmB resistance. A few prominent phenotypes of PMP3 delete strain, namely, defective actin polarity, impaired salt tolerance, and reduced rate of endocytosis are not related to its AmB-sensitivity. The AmB resistance mechanisms reported so far mainly involve reduction in ergosterol content or alterations in cell wall[7,8,9,10,11]. We show that certain prominent phenotypes of PMP3 delete www.nature.com/scientificreports strain, namely defects in salt tolerance, actin polarity and endocytosis, are not responsible for AmB-sensitivity of this strain. We demonstrate that modulation of AmB resistance by PMP3 is mediated through sphingolipid biosynthetic pathway

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