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Filamentous growth is a hallmark of  C .  albicans  pathogenicity compared to less-virulent ascomycetes. A multitude of transcription factors regulate filamentous growth in response to specific environmental cues. Our work, however, suggests the evolutionary history of  C .  albicans  that resulted in its filamentous growth plasticity may be tied to a change in the general transcription machinery rather than transcription factors and their specific targets. A key genomic difference between  C .  albicans  and its less-virulent relatives, including its closest relative  C .  dubliniensis , is the unique expansion of the  TLO  (TeLOmere-associated) gene family in  C .  albicans . Individual Tlo proteins are fungal-specific subunits of Mediator, a large multi-subunit eukaryotic transcriptional co-activator complex. This amplification results in a large pool of ‘free,’ non-Mediator associated, Tlo protein present in  C .  albicans , but not in  C .  dubliniensis  or other ascomycetes with attenuated virulence. We show that engineering a large ‘free’ pool of the  C .  dubliniensis  Tlo2 (CdTlo2) protein in  C .  dubliniensis , through overexpression, results in a number of filamentation phenotypes typically associated only with  C .  albicans . The amplitude of these phenotypes is proportional to the amount of overexpressed CdTlo2 protein. Overexpression of other C.  dubliniensis  and  C .  albicans  Tlo proteins do result in these phenotypes. Tlo proteins and their orthologs contain a Mediator interaction domain, and a potent transcriptional activation domain. Nuclear localization of the CdTlo2 activation domain, facilitated naturally by the Tlo Mediator binding domain or artificially through an appended nuclear localization signal, is sufficient for the CdTlo2 overexpression phenotypes. A  C .  albicans med3  null mutant causes multiple defects including the inability to localize Tlo proteins to the nucleus and reduced virulence in a murine systemic infection model. Our data supports a model in which the activation domain of ‘free’ Tlo protein competes with DNA bound transcription factors for targets that regulate key aspects of  C .  albicans  cell physiology.

Amplification of TLO Mediator Subunit Genes Facilitate Filamentous Growth in Candida Spp.