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Vol. 13, Issue 12, 4414-4428, December 2002
and
Institute of *Biochemistry, and Fungal sphingolipids contain ceramide with a very-long-chain fatty
acid (C26). To investigate the physiological significance of the
C26-substitution on this lipid, we performed a screen for mutants that
are synthetically lethal with ELO3. Elo3p is a component of the ER-associated fatty acid elongase and is required for the final
elongation cycle to produce C26 from C22/C24 fatty acids. elo3Food-Chemistry and
Technology, Graz University of Technology, A-8010 Graz, Austria,
and §Department of Medicine, Division of Biochemistry,
University of Fribourg, CH-1700 Fribourg, Switzerland
mutant cells thus contain C22/C24- instead of
the natural C26-substituted ceramide. We now report that under these
conditions, an otherwise nonessential, but also fungal-specific,
structural modification of the major sterol of yeast, ergosterol,
becomes essential, because mutations in ELO3 are
synthetically lethal with mutations in ERG6. Erg6p
catalyzes the methylation of carbon atom 24 in the aliphatic side chain
of sterol. The lethality of an elo3 erg6 double
mutant is rescued by supplementation with ergosterol but not with
cholesterol, indicating a vital structural requirement for the
ergosterol-specific methyl group. To characterize this structural
requirement in more detail, we generated a strain that is temperature
sensitive for the function of Erg6p in an elo3 mutant
background. Examination of raft association of the GPI-anchored Gas1p
and plasma membrane ATPase, Pma1p, in the conditional elo3
erg6ts double mutant, revealed a specific
defect of the mutant to maintain raft association of preexisting Pma1p.
Interestingly, in an elo3 mutant at 37°C, newly
synthesized Pma1p failed to enter raft domains early in the
biosynthetic pathway, and upon arrival at the plasma membrane was
rerouted to the vacuole for degradation. These observations indicate
that the C26 fatty acid substitution on lipids is important for
establishing raft association of Pma1p and stabilizing the protein at
the cell surface. Analysis of raft lipids in the conditional mutant
strain revealed a selective enrichment of ergosterol in detergent-resistant membrane domains, indicating that specific structural determinants on both sterols and sphingolipids are required
for their association into raft domains.
Both authors contributed equally to this work.
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