부산대학교 도서관

The ability of the fungus Candida albicans to filament and form biofilms contributes to its burden as a leading cause of hospital-acquired infections. Biofilm development involves an interconnected transcriptional regulatory network (TRN) consisting of nine transcription factors (TFs) that bind both to their own regulatory regions and to those of the other network TFs. Here, we show that seven of the nine TFs in the C. albicans biofilm network contain prion-like domains (PrLDs) that have been linked to the ability to form phase-separated condensates. Construction of PrLD mutants in four biofilm TFs reveals that these domains are essential for filamentation and biofilm formation in C. albicans. Moreover, biofilm PrLDs promote the formation of phase-separated condensates in the nuclei of live cells, and PrLD mutations that abolish phase separation (such as the removal of aromatic residues) also prevent biofilm formation. Biofilm TF condensates can selectively recruit other TFs through PrLD-PrLD interactions and can co-recruit RNA polymerase II, implicating condensate formation in the assembly of active transcriptional complexes. Finally, we show that PrLD mutations that block the phase separation of biofilm TFs also prevent filamentation in an in vivo model of gastrointestinal colonization. Together, these studies associate transcriptional condensates with the regulation of filamentation and biofilm formation in C. albicans, and highlight how targeting of PrLD-PrLD interactions could prevent pathogenesis by this species. Author summary: The fungus C. albicans is a prevalent cause of life-threatening infections due, in large part, to its ability to form drug-recalcitrant biofilms on biotic or abiotic surfaces. Biofilm formation is controlled by a network of nine TFs that act in combination to regulate their own expression as well as that of downstream genes. We show that seven of the nine master biofilm TFs contain PrLDs, domains that have previously been shown to promote phase separation into a dense phase together with a more dilute surrounding phase. Importantly, disruption of the phase separation capacity of TFs by mutation of select PrLD residues blocks TF function both in vitro and during host colonization. PrLDs also promote the interaction of TFs with RNA polymerase II indicating that they can recruit key components of the cell's transcriptional machinery. We therefore propose that TF PrLDs are integral to C. albicans biofilm formation due to their ability to promote protein-protein interactions and phase separation, and that the coordinated assembly of these complexes drives gene expression programs. [ABSTRACT FROM AUTHOR]