Disease relevance of FKS1

• We and others have defined the Saccharomyces cerevisiae FKS1 gene by recessive mutations resulting in 100-1000-fold hypersensitivity to FK506 and CsA (as compared to wild type), but which do not affect sensitivity to a variety of other antifungal drugs [1].
• The clinical C. albicans mutants were less susceptible to caspofungin in the disseminated candidiasis model, and GS inhibition profiles and DNA sequence analyses were consistent with a homozygous fks1 mutation [2].

High impact information on FKS1

• Rho1p copurified with beta(1-->3)glucan synthase and associated with the Fks1p subunit of this complex in vivo [3].
• The PKC1-activated mitogen-activated protein kinase cascade is not required for depolarization, but rather for repolarization of the actin cytoskeleton and FKS1 [4].
• The redistribution of FKS1 is dependent on the actin cytoskeleton [4].
• In Saccharomyces cerevisiae, mutations in FKS1 confer hypersensitivity to the immunosuppressants FK506 and cyclosporin A, while mutations in ETG1 confer resistance to the cell-wall-active echinocandins (inhibitors of 1,3-beta-D-glucan synthase) and, in some cases, concomitant hypersensitivity to the chitin synthase inhibitor nikkomycin Z [5].
• The FKS1 and ETG1 genes were cloned by complementation of these phenotypes and were found to be identical [5].

Chemical compound and disease context of FKS1

• The yeast FKS1 gene encodes a novel membrane protein, mutations in which confer FK506 and cyclosporin A hypersensitivity and calcineurin-dependent growth [1].

Biological context of FKS1

• Yeast GS is composed of a putative catalytic subunit encoded by FKS1 and FKS2 and a regulatory subunit encoded by RHO1 [6].
• Analysis of fks1 delta mutants showed a partial K1 killer toxin-resistant phenotype and a 30% reduction in alkali-soluble beta-1,3-glucan that was accompanied by a modest reduction in beta-1,6-glucan [7].
• Up-regulation of genes encoding glycosylphosphatidylinositol (GPI)-attached proteins in response to cell wall damage caused by disruption of FKS1 in Saccharomyces cerevisiae [8].
• Deletion and replacement analysis of the promoter regions identified Rlm1-binding sequences as being responsible for the up-regulation following disruption of FKS1 [8].
• Removal of the cell wall does not inhibit internalization, suggesting that the function of Rho1 and Fks1 in endocytosis is not through cell wall synthesis or structural integrity [9].

Anatomical context of FKS1

• FKS1 and FKS2 are alternative subunits of the glucan synthase complex, which is responsible for synthesizing 1,3-beta-glucan chains, the major structural polymer of the Saccharomyces cerevisiae cell wall [10].

Associations of FKS1 with chemical compounds

• Previous work has shown that the FKS1 gene encodes a 215-kDa integral membrane protein (Fks1p) which mediates sensitivity to the echinocandin class of antifungal glucan synthase inhibitors and is a subunit of this enzyme [11].
• Induction of FKS2 expression in response to pheromone, CaCl2, or loss of FKS1 function requires the Ca2+/calmodulin-dependent protein phosphatase calcineurin [10].
• Alternatively, Fks1p and Fks2p could actively participate in the biosynthesis of both polymers as beta-glucan transporters [7].
• The remaining two genes were up-regulated by doxycycline, suggesting that a transcription factor other than Rlm1 is involved in their response to disruption of FKS1 [8].
• We have previously shown that growth of fks1 null mutants is highly sensitive to the calcineurin inhibitors FK506 and cyclosporin A [11].

Physical interactions of FKS1

• Gel overlay analysis indicated that an unmodified form of GST-Rho1p fails to interact with Fks1p [12].

Other interactions of FKS1

• PXL1 also displays genetic interactions with the Rho1 effector FKS1 [13].
• These results suggest that distinct networks regulate the two effector proteins of Rho1p, Fks1p and Pkc1p [6].
• Fks1p and Fks2p are related proteins thought to be catalytic subunits of the beta-1,3-glucan synthase [7].
• Therefore, a double mutant in calcineurin (CNB1) and FKS1 is inviable due to a deficiency in FKS2 expression [10].
• Disruption of FKS1 reduces the glucan content of the cell wall, increases chitin content and activates the expression of CWP1, which encodes a glycosylphosphatidylinositol (GPI)-dependent cell wall protein [8].

Analytical, diagnostic and therapeutic context of FKS1

• The CND1 gene was cloned, and sequence analysis predicts that it encodes a novel protein 1,876 amino acids in length with multiple membrane-spanning domains [14].
• Northern blotting demonstrated that C. albicans GSC1 and GSL1 but not GSL2 mRNAs were expressed in the growing yeast-phase cells [15].
• In order to identify essential amino acid residues responsible for the sensitivity, each of the 10 non-conserved amino acids of Fks1p was substituted into the corresponding amino acid of Fks2p by site-directed mutagenesis [16].

References