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The carbohydrate utilization regulator Cbr1 coordinates nutrient-specific gene activation with selective carbon catabolite repression in a basidiomycete yeast [1]

['Brandon Reyes-Chavez', 'Plant Pathology', 'Plant-Microbe Biology Section', 'School Of Integrative Plant Science', 'Cornell University', 'Ithaca', 'New York', 'United States Of America', 'Microbiology Department', 'Joshua D. Kerkaert']

Date: 2026-09 

Cells must sense and respond to nutrients to survive. To efficiently grow in mixed carbon environments, microbes repress genes necessary to utilize carbon sources that require substantial resources to catabolize when a simpler carbon source, such as glucose, is present. This process is known as carbon catabolite repression. Canonically, in fungi, nutrient sensing transcriptional networks are composed of carbon source-specific transcription factors that activate carbon source utilization genes and carbon catabolite repression regulators, which broadly repress all nonpreferred carbon source utilization genes when a preferred carbohydrate is present. In contrast to this model, we identified a transcription factor (Cbr1) in the basidiomycete yeast Rhodotorula (Rhodosporidium) toruloides that specifically inhibits glucose-mediated repression of disaccharide and proline utilization, presenting a mechanism of tailored carbon catabolite repression regulation that combats a negative feedback loop formed when glucose is released during disaccharide utilization. Cbr1 is also required for cellobiose, gentiobiose, carboxylic acid, and fucose utilization. Using transcriptomic and molecular analyses, we demonstrated that catabolism of these carbon sources is not metabolically linked, but genes necessary for their utilization are coactivated by Cbr1 in response to each of the carbon sources. This coactivation suggests R. toruloides may encounter these carbon sources together, potentially during complex interactions among microbes in nature. Coregulation of nutrient-specific gene activation and carbon catabolite repression by a transcription factor establishes a previously uncharacterized mechanism for building nutrient sensing transcriptional networks in fungi. Characterizing diverse nutrient sensing regulatory mechanisms is critical for understanding resource acquisition during fungal pathogenesis, where carbon catabolite repression is important for virulence and drug tolerance, and metabolically engineering fungi for green biotechnology.

Funding: This work was supported by a grant from the National Institute of General Medical Sciences ( https://www.nigms.nih.gov/ ) of the National Institutes of Health (NIH) ( https://www.nih.gov/ ) under Award Number R35GM150926 to L.B.H. J.D.K. was supported by NIH Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant 5T32AI145821-03 from the National Institute of Allergy and Infectious Diseases ( https://www.niaid.nih.gov/ ). The funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability: Raw RNAseq data is available in GEO at the NCBI through accession numbers GSE293943 (standard RNAseq) and GSE313844 (3’ RNAseq). Processed RNAseq data is available in S4, S5, and S7-S10 Datas. The numerical values used to generate all other graphs are in S2 Data. Strains constructed in this study are available upon request to the Cornell University Center for Technology Licensing ( mta-ctl@cornell.edu ).

Further investigation of Cbr1 demonstrated this transcription factor inhibits carbon catabolite repression specifically of disaccharide and proline utilization genes. This role for Cbr1 contrasts with previously identified regulatory mechanisms of carbon catabolite repression, which regulate utilization of all nonpreferred carbon sources. Taken together, the diverse roles of Cbr1 in R. toruloides metabolic regulation present a previously uncharacterized mechanism of carbon catabolite repression and nutrient sensing transcriptional network composition in fungi.

Cellulose is the most abundant plant biomass component and is composed of glucose chains linked by β-1,4-glycosidic bonds [ 35 ]. R. toruloides can utilize the disaccharide cellulose building block, cellobiose [ 36 ]. We identified a transcription factor, Cbr1, required for cellobiose utilization. Cbr1 is homologous to the cellulose degradation regulator CLR-2/ClrB in Ascomycetes [ 37 ], but the role of Cbr1 is significantly expanded in R. toruloides, elucidating alternative mechanisms of building carbon utilization regulatory networks in fungi. Unlike CLR-2/ClrB, Cbr1 is also required for gentiobiose, tricarboxylic acid (TCA) cycle intermediate, and fucose utilization. Cellobiose/gentiobiose, fucose, and TCA cycle intermediates are not catabolized through similar pathways, potentially suggesting R. toruloides may inhabit an ecological niche in which these carbon sources are frequently found together, possibly through cooperation with or exploitation of saprophytic filamentous fungi.

To address this knowledge gap, we investigated genetic mechanisms regulating carbon utilization in the basidiomycete yeast Rhodotorula toruloides (previously Rhodosporidium toruloides). While R. toruloides is in a different phylogenetic class than some of the more established basidiomycete human and plant pathogens, like Cryptococcus neoformans, Puccinia graminis, or Ustilago maydis, Rhodotorula species are an emerging cause of opportunistic infections in humans and animals that are frequently resistant to antifungal drugs [ 17 – 19 ]. Rhodotorula infections are often associated with central venous catheter use in immunosuppressed individuals, and meningeal, skin, ocular, peritoneal, and prosthetic joint infections can occur in healthy individuals [ 18 , 20 , 21 ]. Recent studies of Ascomycete yeast species have established these organisms have a range of carbon utilization repertoires, from specialists capable of consuming only a small range of carbohydrates to generalists that have a much broader carbon utilization repertoire [ 22 ]. R. toruloides is a generalist that can consume most soluble breakdown products of plant biomass [ 23 , 24 ]. R. toruloides can also accumulate up to 70% of its biomass as fatty acids in conditions in which carbon is abundant, but other nutrients are limiting and produces useful secondary metabolites, such as carotenoids [ 25 – 31 ]. This makes R. toruloides an excellent choice for metabolic engineering [ 32 ], where understanding the regulation of carbon metabolism is critical [ 33 , 34 ].

Many devastating human, animal, and plant pathogens fall outside of the Ascomycete phylum [ 11 ]. Genetic mechanisms through which these fungi activate genes necessary to utilize nonpreferred carbon sources and repress these genes in the presence of more preferred carbon sources are significantly less well studied. Basidiomycetes diverged from Ascomycetes approximately 400 million years ago and represent over 30% of described fungi [ 12 , 13 ]. Recent studies in Basidiomycete pathogens have demonstrated that understanding the regulation of carbon utilization in this phylum is critical, since accurately regulating carbon metabolism is not only important for virulence but also changes the efficacy of antifungal drug treatments [ 14 – 16 ].

Cells must sense and respond to nutrients to successfully grow and divide using the resources available. For fungi, nutrient sensing is critical to establish fungal colonies, compete with other microbes, and establish pathogenic and symbiotic relationships with plants and animals. Most work characterizing genetic pathways regulating carbon source utilization in fungi has been performed in the Ascomycete phylum [ 1 , 2 ]. In these fungi, a network of carbon source-specific transcription factors activates genes necessary for utilization of available carbon [ 3 ]. However, in a mixed carbon environment, it is not necessarily energetically optimal to simultaneously consume all available carbon sources. Thus, when a more preferred carbon source, such as glucose, is available, a process known as carbon catabolite repression broadly downregulates expression of genes required for utilization of all less preferred carbon sources [ 1 , 3 – 10 ].

Results

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003983

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