Disease relevance of FUR4

• Among these, Tpn1, Fur4 and the one encoded by yOR071c were found to contribute significantly to 5-FC toxicity, thus revealing alternative entry routes for 5-FC via other cytosine/adenine permease homologues [1].
• The uracil permease gene of the yeast Saccharomyces cerevisiae was cloned on a hybrid plasmid which replicates autonomously in both yeast and Escherichia coli [2].
• Our results show that long chain bases do not contribute to the inactivation of Fur4p transport activity after heat stress, but they are essential for some later, but unknown, process that leads to degradation of the protein [3].

High impact information on FUR4

• We have recently reported that the yeast plasma membrane uracil permease undergoes cell-surface ubiquitination, which is dependent on the Npi1/Rsp5 ubiquitin-protein ligase [4].
• The data presented here show that ubiquitination and endocytosis of uracil permease are impaired in yeast cells lacking the Doa4p ubiquitin-isopeptidase [4].
• The behaviour of the transformant shows not only an expression of the uracil permease gene in the heterologous membrane but also that the transport of uracil is active and coupled to the energy furnishing system of the heterologous host [5].
• A piece of DNA of the yeast Saccharomyces cerevisiae complementing the uracil permease gene was introduced into a plasmid able to replicate autonomously in Schizosaccharomyces pombe [5].
• Slm1 and slm2 are novel substrates of the calcineurin phosphatase required for heat stress-induced endocytosis of the yeast uracil permease [6].

Biological context of FUR4

• The results indicated that the translocation points are located close to the FUR4 locus on chromosome II and close to the RAD57 locus on chromosome IV [7].
• We therefore propose that ubiquitination of uracil permease acts as a signal for endocytosis of the protein that is subsequently degraded in the vacuole [8].
• The DNA sequence of a 2967 bp fragment located near the centromere of chromosome II, between the CEN2 and FUR4 genes, was determined [9].
• A PEST-like sequence mediates phosphorylation and efficient ubiquitination of yeast uracil permease [10].
• Overexpression of this permease and specific antibodies were used to show that uracil permease undergoes neither N-linked glycosylation nor proteolytic processing [11].

Anatomical context of FUR4

• Uracil permease is a multispanning protein of the Saccharomyces cerevisiae plasma membrane which is encoded by the FUR4 gene and produced in limited amounts [11].
• In cells with low levels of Rsp5p, Fur4p can be still diverted from the Golgi apparatus but does not reach the vacuolar lumen, being instead missorted to the vacuolar membrane [12].
• In vivo insertion of the hybrid protein bearing the first signal anchor sequence of uracil permease into the endoplasmic reticulum membrane was severely blocked in sec61 and sec62 translocation mutants [11].
• Immunofluorescent analysis showed that antibodies to the last 10 amino acids of uracil permease bind to detergent-treated protoplasts, but not to intact ones [13].
• Carboxypeptidase digested the C-terminus of uracil permease inserted into the sealed dog-pancreas microsomes [13].

Associations of FUR4 with chemical compounds

• Uracil uptake by Saccharomyces cerevisiae is mediated by the FUR4-encoded uracil permease [14].
• Even though the FUI1 gene has a multicopy suppressor effect on uracil transport, its product does not seem to be involved in this transport, in contrast to the FUR4 gene product which is involved in uridine transport [15].
• Correct luminal delivery is restored by the biosynthetic addition of a single ubiquitin, suggesting that the ubiquitylation of Fur4p serves as a specific signal for sorting to the luminal vesicles of the multivesicular bodies [12].
• Growth inhibition of Saccharomyces cerevisiae by the immunosuppressant leflunomide is due to the inhibition of uracil uptake via Fur4p [16].
• The allantoin and uracil permease gene sequences of Saccharomyces cerevisiae are nearly identical [17].

Physical interactions of FUR4

• Direct sorting of the yeast uracil permease to the endosomal system is controlled by uracil binding and Rsp5p-dependent ubiquitylation [12].

Other interactions of FUR4

• The ubiquitin-permease conjugates that are readily demonstrated in wild type cells were barely detectable in npi1 mutant cells, indicating that uracil permease may be a physiological substrate of the Npi1p ubiquitin ligase [8].
• Thus, the growth inhibition by leflunomide seen in a S. cerevisiae ura3 auxotroph is due to the inhibition of the entry of exogenous uracil via the Fur4 uracil permease [16].
• After the observation that FUR4 was closely linked to GAL10, one of the three genes forming the gal cluster (Bassel and Mortimer 1971), we could determine precisely the position of the gene on chromosome II [18].
• Gap1p is thus ubiquitinated differently from the proteins targeted by ubiquitination for proteolysis by the proteasome, but in the same manner as the uracil permease, also subject to ubiquitin-dependent endocytosis [19].
• These data suggest that Fur4p undergoes Doa4p-dependent deubiquitination prior to vacuolar degradation [20].

Analytical, diagnostic and therapeutic context of FUR4

• We have used in vivo pulse labeling and immunoprecipitation to show that the uracil permease is phosphorylated [21].
• Uracil permease is degraded in the vacuole, since pep4 mutant cells lacking vacuolar protease activities accumulated large amounts of uracil permease, which was located within the vacuole by immunofluorescence [22].
• In the present paper, the role of the three charged residues present in the membrane-spanning regions of Fur4p was further investigated by using site-directed mutagenesis [23].
• This result suggests that ligation to ubiquitin could be a signal for uracil permease degradation [24].

References