The Role of Candida albicans Transcription Factor RLM1 in Response to Carbon Adaptation

Abstract

Candida albicans is the main causative agent of candidiasis and one of the most frequent causes of nosocomial infections worldwide. In order to establish an infection, this pathogen supports effective stress responses to counter host defenses and adapts to changes in the availability of important nutrients, such as alternative carbon sources. These stress responses have clear implications on the composition and structure of Candida cell wall. Therefore, we studied the impact of lactate, a physiologically relevant carbon source, on the activity of C. albicans RLM1 transcriptional factor. RLM1 is involved in the cell wall integrity pathway and plays an important role in regulating the flow of carbohydrates into cell wall biosynthesis pathways. The role of C. albicans RLM1 in response to lactate adaptation was assessed in respect to several virulence factors, such as the ability to grow under cell wall damaging agents, filament, adhere or form biofilm, as well as to immune recognition. The data showed that growth of C. albicans cells in the presence of lactate induces the secretion of tartaric acid, which has the potential to modulate the TCA cycle on both the yeast and the host cells. In addition, we found that adaptation of C. albicans cells to lactate reduces their internalization by immune cells and consequent % of killing, which could be correlated with a lower exposure of the cell wall β-glucans. In addition, absence of RLM1 has a minor impact on internalization, compared with the wild-type and complemented strains, but it reduces the higher efficiency of lactate grown cells at damaging phagocytic cells and induces a high amount of IL-10, rendering these cells more tolerable to the immune system. The data suggests that RLM1 mediates cell wall remodeling during carbon adaptation, impacting their interaction with immune cells.

FDA Approved Drug Library Screening Identifies Robenidine as a Repositionable Antifungal

“…Gene expression analysis performed in cells growing under robenidine treatment identified the transcription factor Rlm1, which was significantly upregulated upon robenidine treatment. Rlm1 is reported to be involved in cell wall biogenesis for maintenance of cell wall integrity (Alam et al, 2011;Delgado-Silva et al, 2014;Oliveira-Pacheco et al, 2018). The increase of mannan component and decrease of chitin content were also consistent with the role of Rlm1 on regulation of cell wall integrity (Delgado-Silva et al, 2014).…”

“…RNA-seq analysis revealed that the expression of the transcription factor Rlm1 (Supplementary Figure S4), a downstream effector of Mkc1, was increased up to eightfold after treatment with robenidine for 90 min. Rlm1 plays an important role in maintenance of cell wall integrity (Oliveira-Pacheco et al, 2018). Interestingly, the expression of RLM1 decreased when C. albicans was exposed to robenidine over a prolonged period of time (3-9 h).…”

An expanded cell wall damage signaling network is comprised of the transcription factors Rlm1 and Sko1 in Candida albicans

“…Despite this, Rlm1 was shown to regulate a small fraction of caspofungin-responsive genes, and its activators remain unknown [7]. Recently, Rlm1 was shown to play a role in cell wall remodeling and filamentation in C. albicans when yeast-form cells were grown in lactate as a carbon source [13].…”

“…Recently, Rlm1 was shown to play a role in cell wall remodeling and filamentation in C . albicans when yeast-form cells were grown in lactate as a carbon source [ 13 ].…”

Adapting to survive: How Candida overcomes host-imposed constraints during human colonization

“…Some of these play important roles in hyphal formation, adhesion, drug resistance, and matrix production (all intrinsic characteristics of biofilms), as well as in stress adaptation. It is not surprising, then, that adaptation to specific environmental niches modulates the ability of cells to form biofilms and, consequently, to resist antifungals [54,55,58,59,[182][183][184].…”