9.A.26 The Lipid-translocating Exporter (LTE) Family

The LTE family includes members (see below) which in S. cerevisiae have been implicated in lipid or lipid moiety flipping from the inner leaflet to the outer leaflet of the cytoplasmic membrane bilayer. These proteins have 280-500 aas and 7 putative TMSs sometimes with a sizable hydrophilic loop between TMSs 5 and 6. Several have hydrophilic N- or C-terminal extensions. Their distribution is restricted to the fungal kingdom.

Ceramide is produced by the condensation of a long chain base with a very long chain fatty acid. In Saccharomyces cerevisiae, one of the two major long chain bases is called phytosphingosine (PHS). PHS has been shown to cause toxicity in tryptophan auxotrophic strains of yeast because this bioactive ceramide precursor causes diversion of the high affinity tryptophan permease Tat2 (TC# 2.A.3.10.8) to the vacuole rather than the plasma membrane. Loss of the integral membrane protein Rsb1 increased PHS sensitivity, which was suggested to be due to this protein acting as an ATP-dependent long chain base efflux protein. Loss of the genes encoding the ATP-binding cassette transporter proteins Pdr5 and Yor1 elevate PHS tolerance. This increased resistance was suggested to be due to increased expression of RSB1.

Johnson et al. (2010) provided an alternative view of PHS resistance influenced by Rsb1 and Pdr5/Yor1. A Δrsb1 cell does not exhibit higher internal levels of PHS compared with isogenic wild-type cells. However, tryptophan transport is increased in Δpdr5 yor1 strains and reduced in Δrsb1 cells. Localization and vacuolar degradation of Tat2 are affected in these genetic backgrounds. Finally, internalization of FM4-64 dye suggests that loss of Pdr5 and Yor1 slows normal endocytic rates. Rsb1, Pdr5, and Yor1 thus may regulate the endocytosis of Tat2 and other membrane transporter proteins (Johnson et al., 2010). 

Widespread use of azoles has led to the rapid development of drug resistance in Candida albicans. Rta2p, a membrane protein with 7 transmembrane domains, is involved in calcineurin-mediated azole resistance and sphingoid long-chain base release. A G234S mutant enhanced the therapeutic efficacy of fluconazole against systemic candidiasis and significantly increased the accumulation of dihydrosphingosine by decreasing its release.  G234 of Rta2p is crucial in calcineurin-mediated fluconazole resistance and dihydrosphingosine transport (Zhang et al. 2015).

The transport reaction presumed to be catalyzed by LTE family members is:

lipid or lipid moiety (in) ⇌ lipid or lipid moiety (out)