Abstract
BackgroundThe 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.ResultsInterestingly, 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.ConclusionsThe 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.
Highlights
The nutrient-sensing target of rapamycin (Tor) pathway governs cell growth and is conserved in most eukaryotic organisms from unicellular yeasts to multicellular organisms, including humans
We have investigated gene and genome duplication events that resulted in two Tor homologs in S. cerevisiae, S. pombe, P. ostreatus, and B. dendrobatidis, and the loss of a second Tor homolog following a whole genome duplication event in R. oryzae
Tor is essential for life and is the target of the potent drug rapamycin in fungi, humans, and other eukaryotic organisms [2,12,19,41]
Summary
The nutrient-sensing Tor pathway governs cell growth and is conserved in most eukaryotic organisms from unicellular yeasts to multicellular organisms, including humans. 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 [1,2,3]. In S. cerevisiae and S. pombe, two Tor paralogs form distinct complexes known as Tor Complex 1 (TORC1). Tor Complex 2 (TORC2) [9,10,11,12], while in most other species, including humans, a single Tor protein can populate both complexes [11,12,13,14]. Two Tor paralogs have 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
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