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Review
, 69 (2), 262-91

Cell Wall Integrity Signaling in Saccharomyces Cerevisiae

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Review

Cell Wall Integrity Signaling in Saccharomyces Cerevisiae

David E Levin. Microbiol Mol Biol Rev.

Abstract

The yeast cell wall is a highly dynamic structure that is responsible for protecting the cell from rapid changes in external osmotic potential. The wall is also critical for cell expansion during growth and morphogenesis. This review discusses recent advances in understanding the various signal transduction pathways that allow cells to monitor the state of the cell wall and respond to environmental challenges to this structure. The cell wall integrity signaling pathway controlled by the small G-protein Rho1 is principally responsible for orchestrating changes to the cell wall periodically through the cell cycle and in response to various forms of cell wall stress. This signaling pathway acts through direct control of wall biosynthetic enzymes, transcriptional regulation of cell wall-related genes, and polarization of the actin cytoskeleton. However, additional signaling pathways interface both with the cell wall integrity signaling pathway and with the actin cytoskeleton to coordinate polarized secretion with cell wall expansion. These include Ca(2+) signaling, phosphatidylinositide signaling at the plasma membrane, sphingoid base signaling through the Pkh1 and -2 protein kinases, Tor kinase signaling, and pathways controlled by the Rho3, Rho4, and Cdc42 G-proteins.

Figures

FIG. 1.
FIG. 1.
CWI signaling pathway. Signals are initiated at the plasma membrane (PM) through the cell surface sensors Wsc1, -2, and -3, Mid2, and Mtl1. The extracellular domains of these proteins are highly O-mannosylated. Together with PI4,5P2, which recruits the Rom1/2 GEFs to the plasma membrane, the sensors stimulate nucleotide exchange on Rho1. Relative input of each sensor is indicated by the width of the arrows. Rho1 activates five effectors, including the Pkc1-MAP kinase cascade, the β1,3-glucan synthase (GS), the Bni1 formin protein, the exocyst component Sec3, and the Skn7 transcription factor. Additional regulatory inputs from the Tus1 GEF, the inhibitory Rho1 GAPs, and the Pkh1/2 protein kinases are indicated. Pkh1/2 are activated by phytosphingosine (PHS). The MAP kinase cascade, which is comprised of Bck1, Mkk1/2, and Mpk1, is activated by Pkc1. Several MAP kinase phosphatases downregulate Mpk1. Two transcription factors, Rlm1 and the SBF complex (Swi4/Swi6), are targets of the MAP kinase.
FIG. 2.
FIG. 2.
Coordinate activation of CWI signaling, Ca2+ signaling, and Skn7 to induce FKS2 expression. Activation of Mpk1 results in stimulation of Rlm1 and Swi4 transcription factors to drive transcription of FKS2 (and other cell wall-related genes) and the Mid1-Cch1 Ca2+ channel. Channel activation leads to stimulation of the Ca2+-calmodulin-dependent protein phosphatase calcineurin. Dephosphorylation of the Crz1 transcription factor by calcineurin allows its entry into the nucleus. Rho1 may activate the Skn7 transcription factor (hatched line), which drives both expression of the OCH1 gene and stabilization of the Crz1 transcription factor for induction of FKS2. Thus, CWI signaling and Ca2+ signaling coordinately regulate expression of the GS-encoding FKS2 gene at several levels.
FIG. 3.
FIG. 3.
Sln1 branch of the HOG pathway. The Sln1 sensor kinase is autophosphorylated under conditions of low extracellular osmolarity. Sln1 phosphorylates the histidine phosphotransfer protein Ypd1, which phosphorylates both the Skn7 and Ssk1 response regulators. Phospho-Skn7 is the active form of this transcription factor, which binds to the SSRE of OCH1 and probably other cell wall-related genes. Phospho-Ssk1 is the inactive form of this response regulator. Sln1 is inactivated in response to high extracellular osmolarity. This allows the dephosphorylated forms of Ypd1, Ssk1, and Skn7 to accumulate. Dephospho-Skn7 is inactive, whereas dephospho-Ssk1 activates the Hog1 MAP kinase cascade, which stimulates several transcription factors to drive expression of genes to mount the HOG (High Osmoslarity Glycerol) response.
FIG. 4.
FIG. 4.
Phosphoinositide signaling pathway at the plasma membrane (PM). The sequential actions of Stt4 and Mss4 at the cell surface generate PI4,5P2, which recruits Rom2 to the plasma membrane through its PH domain for interaction with the cell surface sensors. The sensors activate Rom2, a GEF for the Rho1 GTPase. Sfk1 appears to be a plasma membrane tethering factor for Stt4. Mss4 cycles between the plasma membrane and the nucleus for reasons that are not yet clear. Yck1 and -2 are plasma membrane-associated casein kinase 1 isoforms that phosphorylate Mss4 and stabilize it at the plasma membrane.
FIG. 5.
FIG. 5.
Model for the regulation of Swi4 by Mpk1. Mpk1 is activated both by cell wall stress and periodically through the cell cycle. Swi6 is the regulatory subunit that complexes with Swi4 to form SBF, a cell cycle-specific transcription factor. During periods other than G1, Swi6 is phosphorylated on Ser160, which causes its exclusion from the nucleus. It is likely that this phosphorylation is catalyzed by Mpk1. Mpk1 also phosphorylates Swi6 in response to cell wall stress. Swi4, the DNA-binding component of SBF, associates with Mpk1 in vitro and may form an alternative transcriptional complex for the regulation of some cell wall- and morphogenesis-related genes, notably FKS2 and PCL1.
FIG. 6.
FIG. 6.
Several signaling pathways converge to drive actin polarization. Rho1 and -2, the regulators of the CWI signaling pathway, influence actin through the Bni1 (and probably Bnr1) formin protein as well as through the Pkc1-activated MAP kinase cascade. Rho3 and -4 and Cdc42 drive actin polarization through Bni1 and Bnr1. The Pkh1/2 protein kinases are activated by phytosphingosine (PHS) and contribute to actin polarization in at least two ways—activation of Pkc1 and of Ypk1/2. Ypk2 (and presumably Ypk1) also require phosphorylation by Tor2 to be active. The action of the PI4P 5-kinase Mss4 at the plasma membrane generates PI4,5P2, which recruits both the Rho1 GEF Rom2 and the Slm1/2 proteins to the plasma membrane through their PH domains. Slm1 and -2 must also be phosphorylated by Tor2 plasma membrane association. Their role in actin polarization is not understood, but they may represent a node for the integration of signals from Mss4 and Tor2.

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