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: antifungal; cell wall integrity; gene expression; mitogen-activated protein kinase (MAPK); signal transduction; transcription.

Figure 1

The cell wall integrity (CWI) signaling pathway. Cell wall damage is sensed (wave arrows) at the plasma membrane through cell-surface proteins that stimulate nucleotide exchange on Rho1 and activation of Pkc1. The main role of activated Pkc1 is to trigger the MAPK module (Bck1, Mkk1/Mkk2 and Slt2). Once phosphorylated, the MAPK Slt2 activates two different transcription factors, SBF (Swi4/Swi6) and Rlm1. Cell wall damage caused by Congo red (CR) is sensed mainly through Mid2 to activate the CWI pathway; Zymolyase (Zym) mediated cell wall stress requires Hkr1 sensor and elements of the Sho1 branch of the high-osmolarity glycerol (HOG) pathway to activate Rho1; Caspofungin (Cas) is sensed through Wsc1 leading to the activation of the CWI pathway and parallel inhibition of protein kinase A (PKA) signaling (solid lines) Modulatory mechanisms of CWI signaling are represented with broken lines. Rlm1 elicits transcriptional positive feedback loops on the expression of RLM1 and SLT2. In contrast, attenuation of the CWI pathway requires negative retrophosphorylation feedback loops mediated by Slt2 on Rom2 and Mkk1/2 and the Rlm1-dependent transcriptional induction of the Slt2 phosphatases Ptp2 and Msg5. In addition, other Slt2 phosphatases like Ptp3, Sdp1 and Ptc1 and ubiquitination of Pkc1 by Ubp3 also contribute to attenuate the induction of CWI pathway. Arrows and T symbols represent activation (positive) and inhibitory (negative) events, respectively.