Conservation, duplication, and loss of the Tor signaling pathway in the fungal kingdom

BMC Genomics, Sep 2010

Background The nutrient-sensing Tor pathway governs cell growth and is conserved in nearly all eukaryotic organisms from unicellular yeasts to multicellular organisms, including humans. Tor is the target of the immunosuppressive drug rapamycin, which in complex with the prolyl isomerase FKBP12 inhibits Tor functions. Rapamycin is a gold standard drug for organ transplant recipients that was approved by the FDA in 1999 and is finding additional clinical indications as a chemotherapeutic and antiproliferative agent. Capitalizing on the plethora of recently sequenced genomes we have conducted comparative genomic studies to annotate the Tor pathway throughout the fungal kingdom and related unicellular opisthokonts, including Monosiga brevicollis, Salpingoeca rosetta, and Capsaspora owczarzaki. Results Interestingly, the Tor signaling cascade is absent in three microsporidian species with available genome sequences, the only known instance of a eukaryotic group lacking this conserved pathway. The microsporidia are obligate intracellular pathogens with highly reduced genomes, and we hypothesize that they lost the Tor pathway as they adapted and streamlined their genomes for intracellular growth in a nutrient-rich environment. Two TOR paralogs are present in several fungal species as a result of either a whole genome duplication or independent gene/segmental duplication events. One such event was identified in the amphibian pathogen Batrachochytrium dendrobatidis, a chytrid responsible for worldwide global amphibian declines and extinctions. Conclusions The repeated independent duplications of the TOR gene in the fungal kingdom might reflect selective pressure acting upon this kinase that populates two proteinaceous complexes with different cellular roles. These comparative genomic analyses illustrate the evolutionary trajectory of a central nutrient-sensing cascade that enables diverse eukaryotic organisms to respond to their natural environments.

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Conservation, duplication, and loss of the Tor signaling pathway in the fungal kingdom

Cecelia A Shertz 0 Robert J Bastidas 0 Wenjun Li 0 Joseph Heitman 0 Maria E Cardenas 0 0 Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, NC 27710 , USA Background: The nutrient-sensing Tor pathway governs cell growth and is conserved in nearly all eukaryotic organisms from unicellular yeasts to multicellular organisms, including humans. Tor is the target of the immunosuppressive drug rapamycin, which in complex with the prolyl isomerase FKBP12 inhibits Tor functions. Rapamycin is a gold standard drug for organ transplant recipients that was approved by the FDA in 1999 and is finding additional clinical indications as a chemotherapeutic and antiproliferative agent. Capitalizing on the plethora of recently sequenced genomes we have conducted comparative genomic studies to annotate the Tor pathway throughout the fungal kingdom and related unicellular opisthokonts, including Monosiga brevicollis, Salpingoeca rosetta, and Capsaspora owczarzaki. Results: Interestingly, the Tor signaling cascade is absent in three microsporidian species with available genome sequences, the only known instance of a eukaryotic group lacking this conserved pathway. The microsporidia are obligate intracellular pathogens with highly reduced genomes, and we hypothesize that they lost the Tor pathway as they adapted and streamlined their genomes for intracellular growth in a nutrient-rich environment. Two TOR paralogs are present in several fungal species as a result of either a whole genome duplication or independent gene/segmental duplication events. One such event was identified in the amphibian pathogen Batrachochytrium dendrobatidis, a chytrid responsible for worldwide global amphibian declines and extinctions. Conclusions: The repeated independent duplications of the TOR gene in the fungal kingdom might reflect selective pressure acting upon this kinase that populates two proteinaceous complexes with different cellular roles. These comparative genomic analyses illustrate the evolutionary trajectory of a central nutrient-sensing cascade that enables diverse eukaryotic organisms to respond to their natural environments. - Background The nutrient-sensing target of rapamycin (Tor) pathway is highly conserved among eukaryotes and governs several essential cellular processes including protein synthesis, ribosome biogenesis, autophagy, and cytoskeletal organization [1-3]. In the fungal kingdom, the Tor pathway has been best studied in the budding yeast Saccharomyces cerevisiae [2-4], the fission yeast Schizosaccharomyces pombe [5,6], and the human pathogen Candida albicans [5-8]. However, little is known about Tor in basal fungal lineages, including the Zygomycota and Chytridiomycota. In S. cerevisiae and S. pombe, two Tor paralogs form distinct complexes known as Tor Complex 1 (TORC1) and Tor Complex 2 (TORC2) [9-12], while in most other species, including humans, a single Tor protein can populate both complexes [11-14]. Interestingly, S. cerevisiae Tor2 can complement the loss of Tor1, but Tor1 cannot complement the loss of Tor2 [15,16]. Two Tor paralogs have also been identified in a metazoan, the silkworm Bombyx mori [17] and three Tor paralogs were identified in the trypanosomatid parasites Leishmania major [18] and the related species Trypanosoma brucei [19], the first reported Tor triumvirates. The ScTORC1 is sensitive to rapamycin and controls protein synthesis, mRNA synthesis and degradation, ribosome biogenesis, and autophagy. TORC2 is insensitive to rapamycin and is involved in the control of actin polarization and cell wall integrity [9,16]. TORC1 consists of Tor1 or Tor2, Kog1 [20], Tco89, and Lst8 [21], while TORC2 contains Tor2, Lst8, Avo1, Avo2, and Figure 1 The Tor pathway in the model fungi Saccharomyces cerevisiae and Schizosaccharomyces pombe. The Tor pathway components investigated in this study in S. cerevisiae (A) and S. pombe (B) are included in this figure. Functional homologs between the two species are indicated in the same shape and color. Sch9, Ypk1, and Gad8 are AGC kinases that are Tor- and PDK-regulated. Avo3 [22] (Figure 1A). Recently, the EGO-GTPase complex and its orthologs were shown to convey amino acid signals for TORC1 activation in yeast, insects, and mammals [23-26]. In S. cerevisiae, immediate effectors of TORC1 include the PP2A-like phosphatase Sit4 [27] and the AGC kinase Sch9 [28]. In S. pombe, Tor participates in other cellular functions including nutrient signaling [29], cell growth and differentiation [30], mitotic commitment [31], and sexual development [11] (Figure 1B). The structure of the Tor proteins is remarkably conserved (Figure 2) and features several domains for protein-protein interactions including N-terminal HEAT (Huntingtin, Elongation factor 3, PP2A A subunit, Tor) repeats [32], a FAT (FRAP, ATM, and TRRAP) domain [33,34], and an FRB (FK506-Rapamycin Binding) [35] domain. The kinase and the FATC (FAT domain at the C-terminus) (...truncated)


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Cecelia A Shertz, Robert J Bastidas, Wenjun Li, Joseph Heitman, Maria E Cardenas. Conservation, duplication, and loss of the Tor signaling pathway in the fungal kingdom, BMC Genomics, 2010, pp. 510, 11, DOI: 10.1186/1471-2164-11-510