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Chapter 9 : Establishment of Cell Identity in Pathogenic Fungi
Category: Fungi and Fungal Pathogenesis
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This chapter examines how cell identity influences mating-type determination, particularly in fungal pathogens. It explores cases where cell identity plays roles outside of mating type, affects cell morphology, and influences pathogenesis. The chapter begins with a description of cell type determination in the budding yeast Saccharomyces cerevisiae and uses this as a platform for exploring mechanisms in the human fungal pathogens Candida albicans and Cryptococcus neoformans as well as the plant fungal pathogen Ustilago maydis. It concludes with a short description of the influence of cell identity on the behaviors of several other plant and human fungal pathogens and how cell identity in fungi is evolving to encompass a more diverse array of fungal behaviors. A fungal pathogen in which cell identity determination has come to the fore is in the basidiomycete fungus C. neoformans. There are two obvious possibilities for specifying haploid cell identity: either the pheromone and pheromone receptor alleles in each mating type have diverged from one another sufficiently to confer pheromone-receptor binding specificity, or there are other factors or mechanisms at play in determining haploid cell types. The authors will continue to discover new strategies undertaken by the pathogenic fungi to develop and integrate multiple cell identities in the effort to survive.
Key Concept Ranking
- Restriction Fragment Length Polymorphism
Cell type determination in S. cerevisiae. (A) The mating-type (MAT) locus of S. cerevisiae contains two alleles (<1 kb). MAT a from a cells encodes the homeodomain regulator a1. MATα from α cells encodes the α-domain protein α1 and the homeodomain protein α2. In diploid cells both MAT a and MAT α are present. (B) The transcriptional regulatory circuit of S. cerevisiae. In a cells the protein a1 is produced but has no known effect, a-specific genes (asg) are constitutively active, and the α-specific genes (αsg) are not expressed. In α cells, α2 represses a -specific genes and α1 activates α-specific genes, thus establishing the α cell type. In a/α diploid cells, α2 continues to repress a-specific genes, but it also interacts with a1 to form a transcriptional regulatory complex that represses haploid-specific genes (hsg), including α1. This repression leads to the specification of the diploid cell type, making further sexual development (i.e., meiosis and sporulation) possible.
Cell type determination in C. albicans. (A) The mating-type-like (MTL) locus of C. albicans (~9 kb) contains transcriptional regulators and three other gene types. MTL a encodes the homeodomain protein a1 and the HMG box protein a 2. MTLα encodes the α-domain protein α1 and the homeodomain protein α2. Both MTL a and MTL α contain diverged alleles of a poly(A) polymerase (PAP), an oxysterol binding protein (OBP), and a phosphotidylinositol kinase (PIK). The roles of PAP, OBP, and PIK in cell type determination are not known. (B) The transcriptional circuit of C. albicans. Cells containing only a information (a/a or a/α at the MTL locus) mate as a cells because the predicted transcription factor a 2 activates genes required for a-type mating. Cells containing only α information (α/α or Δ/α at the MTL locus) mate as α cells because the predicted transcription factor α1 activates genes required for α-type mating. Cells containing both a and α information (a/α at the MTL locus) do not mate with other cells because a1 and α2 work in concert to repress genes required for mating and white-opaque switching. Cells that cannot switch from white to opaque cannot mate, and this switch is repressed by a1-α2.
Cell type determination in U. maydis. (A) There are two independent, unlinked mating-type loci in U. maydis. One locus (a) contains the cell-type-specific pheromone gene mfa1 and pheromone receptor gene pra1 in one allele (a1, ~4.6 kb), and the other allele (a2, ~8.5 kb) contains the pheromone gene mfa2 and pheromone receptor gene pra2. a2 also contains lga2 and rga2, whose products show no similarity to other proteins and play no apparent role in mating but do seem to affect pathogenesis by controlling mitochondrial function ( 4 ). The second locus (b, ~3.6 kb) encodes the homeodomain proteins bE and bW, of which there are 25 different forms, resulting in many different mating types in a tetrapolar mating-type system. (B) Regulation of cell identity in U. maydis. Half circles represent haploid cell surfaces. Haploid cell types are specified by the expression of mfa1 (●) and pra1 (forked receptor on cell surface) or mfa2 (▼) and pra2 (round receptor on cell surface). Soluble pheromones are sensed by surface receptors, activating cell fusion when two cells of the opposite mating type encounter one another. After cell fusion, the components of the b locus (bE and bW) interact with one another in specific combinations (e.g., bW1-bE2) to indicate the dikaryotic state and make the cells competent for further sexual development in corn plants.
Cell type determination in C. neoformans. (A) The mating-type (MAT) locus of C. neoformans is unusually large (>100 kb) and contains many genes whose functions in cell type determination are unknown. A schematic of the MAT locus for C. neoformans var. neoformans (serotype D) is shown. MAT a encodes three copies of the MF a pheromone, the predicted pheromone receptor Ste3a, and the homeodomain protein Sxi2a.MAT encodes three copies of the MFα pheromone, the predicted pheromone receptor Ste3α, and the homeodomain protein Sxi1α. Fifteen additional genes have related but diverged alleles in both MAT a and MAT α. (B) Regulation of cell identity in C. neoformans. The determinants of haploid cell identity are unknown; however, a likely mechanism is the expression of cell-type-specific pheromones and receptors. The expression of MF a and the pheromone receptor STE3 a could specify the a mating type, and the expression of MFα and the pheromone receptor STE3 could specify the α mating type. Soluble pheromones would be sensed by surface receptors, activating cell fusion when two cells of the opposite mating type encounter one another. After cell fusion, the homeodomain proteins Sxi1α and Sxi2a are predicted to interact with one another and regulate transcription through an unknown mechanism to establish the dikaryotic state. The newly designated dikaryon is then competent to undergo extended filamentous growth, meiosis, and sporulation.