Disease relevance of AFR1

• In the present study, we investigated the role of AFR1 in the in vivo response to fluconazole in a mouse model of systemic cryptococcosis [1].

High impact information on AFR1

• AFR1 promotes polarized apical morphogenesis in Saccharomyces cerevisiae [2].
• A plasmid overexpression strategy was used to isolate a new gene, AFR1, which acts together with the receptor C terminus to promote adaptation [3].
• Functional analysis of the interaction between Afr1p and the Cdc12p septin, two proteins involved in pheromone-induced morphogenesis [4].
• Saccharomyces cerevisiae mating pheromones induce production of Afr1p, a protein that negatively regulates pheromone receptor signaling and is required for normal formation of the projection of cell growth that becomes the site of cell fusion during conjugation [4].
• We have recently demonstrated that upregulation of the ATP binding cassette (ABC) transporter-encoding gene AFR1 in Cryptococcus neoformans is involved in the in vitro resistance to fluconazole of this yeast [1].

Biological context of AFR1

• The G protein-coupled alpha-factor receptor promotes polarized growth toward a mating partner. alpha-Factor induces the expression of AFR1, which acts together with the receptor C terminus to promote normal morphogenesis [2].
• The mutant genes contained four distinct point mutations that all occurred between codons 254 and 263, identifying a region that is critical for AFR1 function [5].
• However, AFR1 overexpression did not detectably influence receptor endocytosis or the stability of the receptor protein [6].
• AFR1 overexpression diminished signaling in a strain that lacks the C-terminal phosphorylation sites of the receptor, indicating that AFR1 acts independently of phosphorylation [6].
• Instead, gene dosage studies showed that the effects of AFR1 overexpression on signaling were inversely proportional to the number of receptors [6].

Associations of AFR1 with chemical compounds

• These findings indicate that the upregulation of the AFR1 gene is an important factor in either determining the in vivo resistance to fluconazole or influencing the virulence of C. neoformans [1].

Regulatory relationships of AFR1

• The AFR1 mutants were also defective when expressed as fusions to STE2, the alpha-factor receptor, indicating that the mutant Afr1 proteins are defective in function and not in co-localizing with receptors [5].

Other interactions of AFR1

• AFR1 also showed an interesting genetic relationship with the alpha-factor receptor gene, STE2, suggesting that the receptor is regulated by Afr1p [6].
• Analysis of axl1Delta in combination with other mutations that cause defects in morphogenesis or pheromone sensitivity (e.g. bar1, sst2, afr1) indicated that both phenotypes of ste2-T326 cells, supersensitivity to alpha-factor and the defect in forming pointed projections, contributed to the synergistic mating defect [7].
• Gpa1-mediated adaptation appears to be independent of Afr1, Akr1, and the carboxy-terminus of the pheromone receptor [8].

References