Plasma Membrane Proteolipid 3 Protein Modulates Amphotericin B Resistance throughSphingolipid Biosynthetic Pathway

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