Roles of Candida albicans Mig1 and Mig2 in glucose repression, pathogenicity traits, and SNF1 essentiality

Abstract

Metabolic adaptation is linked to the ability of the opportunistic pathogen Candida albicans to colonize and cause infection in diverse host tissues. One way that C. albicans controls its metabolism is through the glucose repression pathway, where expression of alternative carbon source utilization genes is repressed in the presence of its preferred carbon source, glucose. Here we carry out genetic and gene expression studies that identify transcription factors Mig1 and Mig2 as mediators of glucose repression in C. albicans. The well-studied Mig1/2 orthologs ScMig1/2 mediate glucose repression in the yeast Saccharomyces cerevisiae; our data argue that C. albicans Mig1/2 function similarly as repressors of alternative carbon source utilization genes. However, Mig1/2 functions have several distinctive features in C. albicans. First, Mig1 and Mig2 have more co-equal roles in gene regulation than their S. cerevisiae orthologs. Second, Mig1 is regulated at the level of protein accumulation, more akin to ScMig2 than ScMig1. Third, Mig1 and Mig2 are together required for a unique aspect of C. albicans biology, the expression of several pathogenicity traits. Such Mig1/2dependent traits include the abilities to form hyphae and biofilm, tolerance of cell wall inhibitors, and ability to damage macrophage-like cells and human endothelial cells. Finally, Mig1 is required for a puzzling feature of C. albicans biology that is not shared with S. cerevisiae: the essentiality of the Snf1 protein kinase, a central eukaryotic carbon metabolism regulator. Our results integrate Mig1 and Mig2 into the C. albicans glucose repression pathway and illuminate connections among carbon control, pathogenicity, and Snf1 essentiality.

Generation of Viable Candida albicans Mutants Lacking the “Essential” Protein Kinase Snf1 by Inducible Gene Deletion

“…Essentiality depends on the genetic background, and one caveat is that suppressor mutations may allow growth of cells lacking a normally essential gene. This has recently been reported also for SNF1, which could be deleted in strains that lacked the repressor Mig1 (16). In principle, it is possible that our snf1Δ mutants had acquired such a suppressor mutation after the induced gene deletion to allow visible colony formation within 2 to 3 days.…”

“…Recently, Lagree et al reported that SNF1 could be deleted in mutants lacking the repressor Mig1, indicating that unrestricted repression of Mig1 target genes in the absence of Snf1 explains the presumed essentiality of Snf1 ( 16 ). In our lab, we had also investigated the role of Mig1 in the regulatory network controlled by the SNF1 complex and deleted MIG1 as well as both MIG1 and the functionally related MIG2 in our snf4 Δ mutants.…”

Sugar Phosphorylation Controls Carbon Source Utilization and Virulence of Candida albicans

“…The data represent the average of two independent experiments. (Sexton et al, 2007;Lagree et al, 2020). In fact, deletion of HXK2 increased the expression of glucose transporter genes HGT7, HGT12, and HXT10 (Laurian et al, 2019).…”

“…The central carbon metabolism also plays pivotal roles in C. albicans pathogenicity, since a clear link between carbon control and pathogenicity is observed (Magalhães et al, 2017;Thammahong et al, 2017;Van Ende et al, 2019;Lagree et al, 2020). For example, it is shown that the amount of trehalose in the cells has an effect on filamentation (Serneels et al, 2012).…”

“…Also, enzymes involved in the glucose repression mechanism have an effect on virulence, since two transcription factors, Mig1 and Mig2, involved in this pathway have a dual role. They inhibit the expression of genes necessary for the utilization of alternative carbon sources, and they are responsible for the expression of genes involved in virulence traits, like filamentation and biofilm formation (Lagree et al, 2020). A third example of a link between carbon source and pathogenicity is the fact that glycolysis is upregulated during infections and thereby strongly contributes to the virulence of this pathogenic fungus (Barelle et al, 2006).…”