Chapter 14 : The Cell Wall: Glycoproteins, Remodeling, and Regulation

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This chapter provides an update on cell wall structure and, in particular, cell wall glycoproteins (CWPs), cell wall remodeling, and cell wall regulation. Proteins associated with glycolysis, like enolase and alcohol dehydrogenase, are well-known cytoplasmic proteins but have also been identified at the cell surface; this dual location has led them to be termed “moonlighting” proteins. Glycosylphosphatidylinositol (GPI) anchoring is encountered in every eukaryotic cell, including unicellular yeast cells, several parasites, and highly specialized mammalian cells. Analyses of the and genomes to identify intragenic tandem repeats found a significant enrichment of putative CWPs. Mutants of GAS genes in , , , and had defects in cell wall organization and morphogenesis. Single and double disruption of the Gas orthologues and showed that the enzymatic activity was required for morphogenesis and virulence. The poor resolution of fungal glycoproteins through sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis has prompted alternative nongel technologies to study the complement of proteins in the cell wall. Transcript profiling of cells from in vivo models has identified a number of cell wall-associated genes whose expression is altered compared to those in in vitro-grown cells. As well as being exposed to different stimuli that are independently known to alter expression of cell wall-related genes, the invading fungus will also be under attack by the host’s enzymes and immune cells.

Citation: Munro C, Richard M. 2012. The Cell Wall: Glycoproteins, Remodeling, and Regulation, p 197-223. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch14
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Signaling pathways that regulate cell wall biogenesis and remodeling. The cross-section of a yeast cell prepared by high-pressure freeze substitution transmission electron microscopy demonstrates the outer fibrillar cell surface composed of highly glycosylated glycoproteins surrounding an electron transparent polysaccharide-rich matrix made mainly of glucan with some chitin. In , several integral membrane proteins with glycosylated extracellular domains (Wsc family, Mid2, Mtl1, Msb2, Hkr1, Sho1, and Sln1) act as sensors that respond to changes in cell wall integrity and activate downstream signaling pathways. Msb2, Hkr1, Sln1, and Sho1 also act as osmosensors. In , Msb2 and Sho1 signal to the CEK pathway and Sln1 signals to the HOG pathway. In , the Chk1 histidine kinase and the CEK pathway regulate cell wall biosynthesis, and Δ and Δ mutants have defects in mannan biosynthesis. The PKC pathway is the classical pathway that maintains cell integrity by regulating cell wall biogenesis and remodeling. In , the Wsc and Mid2 sensors signal to Rho1, which activates Pkc1 and the downstream MAP kinase cascade culminating in Slt2 phosphorylation, and in , the orthologous MAP kinase is Mkc1. In addition, in , Rho1 acts as a regulatory subunit of β(1,3)-glucan synthase and Pkc1 is involved in targeting Chs3 to the plasma membrane in response to heat shock. A number of transcription factors, outlined in black, have been identified in as regulating the expression of cell wall-related genes (). Cas5 and Sko1 are involved in the response to echinocandins, and Bcr1 regulates the expression of a number of important adhesins and functions downstream of the TOR signaling pathway. The role of Sko1 in the transcriptional response to caspofungin is dependent on the Psk1 PAS kinase. Crz1 is the transcription factor that lies downstream of the Ca+/calmodulin pathway. In response to elevated intracellular Ca levels, Crz1 becomes dephosphorylated by calcineurin, moves into the nucleus, and activates expression of genes with calcium-dependent response elements within their promoter sequences. In the genes encoding the Crh GPI-anchored protein family are examples of calcium-responsive genes. The PKC, HOG, and Ca signaling all contribute to the regulation of chitin synthesis in . The signaling pathways are based on the paradigm and are predicted to have homologous functions in In some cases rewiring of pathway components has been experimentally demonstrated in and is presented in the schematic. doi:10.1128/9781555817176.ch14.f1

Citation: Munro C, Richard M. 2012. The Cell Wall: Glycoproteins, Remodeling, and Regulation, p 197-223. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch14
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Image of FIGURE 2

Analysis of the predicted O-glycosylation patterns of cell surface glycoproteins using the NetOGlyc 3.1 Server of the Danish Center for Biological Sequence Analysis (http://www.cbs.dtu.dk/services/NetOGlyc/). One representative pattern is used to illustrate the four different categories identified. Asterisks indicate the proteins of group 1 with neither O glycosylation nor N glycosylation predicted. doi:10.1128/9781555817176.ch14.f2

Citation: Munro C, Richard M. 2012. The Cell Wall: Glycoproteins, Remodeling, and Regulation, p 197-223. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch14
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Tandem repeats identified in cell surface glycoproteins. Cell surface glyco-proteins can be classified according to sequence conservation within their intragenic tandem repeats. Four major groups harboring tandem repeats that share common features have been identified: Als, Pir, CFEM, and CxCxYTTYCPL. Representative repeats extracted from the Genome Database (http://www.candidagenome.org/) are shown for the different proteins in each group. Additional sequences from other fungi have been added to some alignments to show the strong conservation between different fungal species. Maggr, G-coupled receptor Mac1; Sacce, ; Zygro, ; Lachth, ; Klula, ; Vanpo, ; Picpa, ; Cangl, . Adapted from references , and . doi:10.1128/9781555817176.ch14.f3

Citation: Munro C, Richard M. 2012. The Cell Wall: Glycoproteins, Remodeling, and Regulation, p 197-223. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch14
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Image of FIGURE 4

glycoprotein families. The proteins are represented by a rectangle (predicted to be GPI anchored) or an oval (not predicted to be GPI anchored). The large group encircled by the dashed and dotted line represents the putative GPI-anchored proteins. Within this group there are 11 families of genes composed only of GPI-anchored proteins (surrounded by solid lines). In addition, there are 10 mixed families (marked with dotted lines) composed of one or more predicted GPI-anchored proteins and one or more non-GPI-anchored proteins. The families are labeled according to the nomenclature in Table 2 . doi:10.1128/9781555817176.ch14.f4

Citation: Munro C, Richard M. 2012. The Cell Wall: Glycoproteins, Remodeling, and Regulation, p 197-223. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch14
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Image of FIGURE 5

Domain organization of glycoprotein families of A common domain organization can be defined for each glycoprotein family. All families display a posttranslational modified domain that is O and/or N glycosylated. The black boxes at the N and the C termini are the signal peptide and the GPI anchor addition signal, respectively. Als proteins consist of tandem immunoglobulin (Ig)-like domains, a β-sheet-rich conserved 127-residue amyloid-forming T region, and a variable number of tandem repeats characteristic of the Als proteins. Iff proteins share a common N-terminal domain of 340 to 350 aa with no predicted specific function. Gas proteins share a GH72 domain (CaZY domain for β(1,3)-glucanosyltransglycosylase, EC 2.4.1) with two catalytic sites located on two glutamic acids at positions 152 and 254 for Pga4/Gas1. The Cys box is the cysteine-enriched module present in Phr1 and -2 and Pga5/Gas2 but not in Phr3 or Pga4/Gas1. Crh proteins share two functional domains, a GH16 domain (CaZY domain for endo-1,3-β-glucanase, EC, and a carbohydrate-binding module (CBM18) for binding chitin, but the last is present only in Utr2/Csf4 and not in Crh11 or Crh12. In the case of Sap proteins, after the propeptide, characteristic of this family, the proteins share an aspartyl protease catalytic domain with two aspartic acid catalytic residues at positions 83 and 380 in Sap9. Four cysteine residues may be responsible for the formation of two disulfide bridges within the catalytic domain. Adapted from references , and . doi:10.1128/9781555817176.ch14.f5

Citation: Munro C, Richard M. 2012. The Cell Wall: Glycoproteins, Remodeling, and Regulation, p 197-223. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch14
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Generic image for table

C. cell wall-associated carbohydrate-active enzymes

Citation: Munro C, Richard M. 2012. The Cell Wall: Glycoproteins, Remodeling, and Regulation, p 197-223. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch14
Generic image for table

species predicted GPI-anchored protein families

Citation: Munro C, Richard M. 2012. The Cell Wall: Glycoproteins, Remodeling, and Regulation, p 197-223. In Calderone R, Clancy C (ed), and Candidiasis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817176.ch14