The CWI Pathway: Regulation of the Transcriptional Adaptive Response to Cell Wall Stress in Yeast

Abstract

Fungi are surrounded by an essential structure, the cell wall, which not only confers cell shape but also protects cells from environmental stress. As a consequence, yeast cells growing under cell wall damage conditions elicit rescue mechanisms to provide maintenance of cellular integrity and fungal survival. Through transcriptional reprogramming, yeast modulate the expression of genes important for cell wall biogenesis and remodeling, metabolism and energy generation, morphogenesis, signal transduction and stress. The yeast cell wall integrity (CWI) pathway, which is very well conserved in other fungi, is the key pathway for the regulation of this adaptive response. In this review, we summarize the current knowledge of the yeast transcriptional program elicited to counterbalance cell wall stress situations, the role of the CWI pathway in the regulation of this program and the importance of the transcriptional input received by other pathways. Modulation of this adaptive response through the CWI pathway by positive and negative transcriptional feedbacks is also discussed. Since all these regulatory mechanisms are well conserved in pathogenic fungi, improving our knowledge about them will have an impact in the developing of new antifungal therapies.Keywords: cell wall integrity; mitogen-activated protein kinase (MAPK); signal transduction; transcription; gene expression; antifungal Cell Wall Organization and Structure in S. cerevisiaeYeast cell integrity depends on the cell wall, an essential structure necessary not only for maintaining morphology but also for protecting cells against environmental stress conditions [1,2]. The cell wall is a macromolecular complex mainly composed of β-1,3-glucan, β-1,6-glucan, chitin and mannoproteins. Chitin, although a minor component, is essential for cell survival. β-1,3-glucan is the most abundant component of the yeast cell wall and serves as a backbone to which the other cell wall components are linked. The reducing ends of β-1,6-glucan and chitin are attached to the non-reducing end of β-1,3-glucan chains by an uncharacterized link and a β-1,4-linkage, respectively [3][4][5]. β-1,6-glucan is also attached to the chitin through β-1,3-linked oligogluco-residues that branch off the glucan. There is also a fraction of free chitin. Cell wall mannoproteins, including those involved in adhesion, cell wall remodeling, structural proteins and somatic antigens [6][7][8][9] can be linked directly to the β-1,3-glucan via alkali-labile bonds [9,10] and indirectly via β-1,6-glucan through a glycosylphosphatidylinositol (GPI) anchor [9,11]. The structure of the fungal cell wall is very well conserved among fungi despite several differences in cell wall composition exist [12]. Among fungal glucans, diversities in configuration, position of glyosidic bonds and branching have been reported [13]. β-1,3-glucan is the major cell wall component and is present in all the fungal species analyzed, whereas other polysaccharides including β-1,3/β-1,4-glucan, β-1,6-glucan or α-1,3-glucan a...

Genetic dissection of the signaling pathway required for the cell wall integrity checkpoint

“…4B). Taking these findings together, the sequential connection of the HOG and CWI pathways is important for the checkpoint, representing another example of sequential regulation of MAP kinases in budding yeast (Leng and Song, 2015;Sanz et al, 2017).…”

Extreme Low Cytosolic pH Is a Signal for Cell Survival in Acid Stressed Yeast

“…Ethanol, also reported to produce damages to CW by affecting its nanomechanical proprieties [46], triggers the HOG pathway that collaborates with PKC/Slt2p pathway for the expression of CWI genes in order to remodelling CW and repair the damages [47]. This connection appears to be made by the action of the Ste11p of the HOG pathway on the Rho1p of the PKC pathway, amplifying the signal for CWI gene expression [48].…”

Aspergillus fumigatus and Aspergillosis in 2019

“…In addition, various signaling pathways associated with these sensors have been implicated in the regulation of cell wall biosynthesis. Among these are the cell wall integrity/protein kinase C pathway, the Ca 2ϩ /calcineurin pathway, a second MAPK cascade, the HOG pathway, and the pHsensing PacC pathway (461)(462)(463). Our understanding of how the compensatory (such as chitin synthesis) or salvage mechanisms in A. fumigatus are integrated with the environment remains elusive.…”