The Evolutionary Rewiring of Ubiquitination Targets Has Reprogrammed the Regulation of Carbon Assimilation in the Pathogenic Yeast Candida albicans
Authors: Sandai Doblin , Yin Zhikang , Selway Laura , Stead David , Walker Janet , Leach Michelle D. , Bohovych Iryna , Ene Iuliana V. , Kastora Stavroula , Budge Susan , Munro Carol A. , Odds Frank C. , Gow Neil A. R. , Brown Alistair J. P. 
Published: December 2012

ABSTRACT

Microbes must assimilate carbon to grow and colonize their niches. Transcript profiling has suggested that
Candida albicans
, a major pathogen of humans, regulates its carbon assimilation in an analogous fashion to the model yeast
Saccharomyces cerevisiae
, repressing metabolic pathways required for the use of alterative nonpreferred carbon sources when sugars are available. However, we show that there is significant dislocation between the proteome and transcriptome in
C. albicans
. Glucose triggers the degradation of the
ICL1
and
PCK1
transcripts in
C. albicans
, yet isocitrate lyase (Icl1) and phosphoenolpyruvate carboxykinase (Pck1) are stable and are retained. Indeed, numerous enzymes required for the assimilation of carboxylic and fatty acids are not degraded in response to glucose. However, when expressed in
C. albicans
,
S. cerevisiae
Icl1 (ScIcl1) is subjected to glucose-accelerated degradation, indicating that like
S. cerevisiae
, this pathogen has the molecular apparatus required to execute ubiquitin-dependent catabolite inactivation.
C. albicans
Icl1 (CaIcl1) lacks analogous ubiquitination sites and is stable under these conditions, but the addition of a ubiquitination site programs glucose-accelerated degradation of CaIcl1. Also, catabolite inactivation is slowed in
C. albicans ubi4
cells. Ubiquitination sites are present in gluconeogenic and glyoxylate cycle enzymes from
S. cerevisiae
but absent from their
C. albicans
homologues. We conclude that evolutionary rewiring of ubiquitination targets has meant that following glucose exposure,
C. albicans
retains key metabolic functions, allowing it to continue to assimilate alternative carbon sources. This metabolic flexibility may be critical during infection, facilitating the rapid colonization of dynamic host niches containing complex arrays of nutrients.

IMPORTANCE
Pathogenic microbes must assimilate a range of carbon sources to grow and colonize their hosts. Current views about carbon assimilation in the pathogenic yeast
Candida albicans
are strongly influenced by the
Saccharomyces cerevisiae
paradigm in which cells faced with choices of nutrients first use energetically favorable sugars, degrading enzymes required for the assimilation of less favorable alternative carbon sources. We show that this is not the case in
C. albicans
because there has been significant evolutionary rewiring of the molecular signals that promote enzyme degradation in response to glucose. As a result, this major pathogen of humans retains enzymes required for the utilization of physiologically relevant carbon sources such as lactic acid and fatty acids, allowing it to continue to use these host nutrients even when glucose is available. This phenomenon probably enhances efficient colonization of host niches where sugars are only transiently available.