Candida albicans Pmr1p, a Secretory Pathway P-type Ca2+/Mn2+-ATPase, Is Required for Glycosylation and Virulence
The cell surface of Candida albicans is the immediate point of contact with the host. The outer layer of the cell wall is enriched in highly glycosylated mannoproteins that are implicated in many aspects of the host-fungus interaction. Glycosylation of cell wall proteins is initiated in the endoplasmic reticulum and then elaborated in the Golgi as the protein passes through the secretory pathway. Golgi-bound mannosyltransferases require Mn2+ as an essential cofactor. In Saccharomyces cerevisiae, the P-type ATPase Pmr1p transports Ca2+ and Mn2+ ions into the Golgi. To determine the effect of a gross defect in glycosylation on host-fungus interactions of C. albicans, we disrupted the PMR1 homolog, CaPMR1. This mutation would simultaneously inhibit many Golgi-located, Mn2+-dependent mannosyltransferases. The Capmr1Δ null mutant was viable in vitro and had no growth defect even on media containing low Ca2+/Mn2+ ion concentrations. However, cells grown in these media progressively lost viability upon entering stationary phase. Phosphomannan was almost completely absent, and O-mannan was severely truncated in the null mutant. A defect in N-linked outer chain glycosylation was also apparent, demonstrated by the underglycosylation of surface acid phosphatase. Consistent with the glycosylation defect, the null mutant had a weakened cell wall, exemplified by hypersensitivity to Calcofluor white, Congo red, and hygromycin B and constitutive activation of the cell integrity pathway. In a murine model of systemic infection, the null mutant was severely attenuated in virulence. These results demonstrate the importance of glycosylation for cell wall structure and virulence of C. albicans. The cell surface of Candida albicans is the immediate point of contact with the host. The outer layer of the cell wall is enriched in highly glycosylated mannoproteins that are implicated in many aspects of the host-fungus interaction. Glycosylation of cell wall proteins is initiated in the endoplasmic reticulum and then elaborated in the Golgi as the protein passes through the secretory pathway. Golgi-bound mannosyltransferases require Mn2+ as an essential cofactor. In Saccharomyces cerevisiae, the P-type ATPase Pmr1p transports Ca2+ and Mn2+ ions into the Golgi. To determine the effect of a gross defect in glycosylation on host-fungus interactions of C. albicans, we disrupted the PMR1 homolog, CaPMR1. This mutation would simultaneously inhibit many Golgi-located, Mn2+-dependent mannosyltransferases. The Capmr1Δ null mutant was viable in vitro and had no growth defect even on media containing low Ca2+/Mn2+ ion concentrations. However, cells grown in these media progressively lost viability upon entering stationary phase. Phosphomannan was almost completely absent, and O-mannan was severely truncated in the null mutant. A defect in N-linked outer chain glycosylation was also apparent, demonstrated by the underglycosylation of surface acid phosphatase. Consistent with the glycosylation defect, the null mutant had a weakened cell wall, exemplified by hypersensitivity to Calcofluor white, Congo red, and hygromycin B and constitutive activation of the cell integrity pathway. In a murine model of systemic infection, the null mutant was severely attenuated in virulence. These results demonstrate the importance of glycosylation for cell wall structure and virulence of C. albicans. Candida albicans is the most common fungal agent of invasive disease in humans (1Pappas P.G. Rex J.H. Lee J. Hamill R.J. Larsen R.A. Powderly W. Kauffman C.A. Hyslop N. Mangino J.E. Chapman S. Horowitz H.W. Edwards J.E. Dismukes W.E. Clin. Infect. Dis. 2003; 37: 634-643Crossref PubMed Scopus (694) Google Scholar, 2Sandven P. Rev. Iberoam. Micol. 2000; 17: 73-81PubMed Google Scholar). 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The study of glycosylation in C. albicans will therefore increase our understanding of the host-fungus interaction. To determine the role of glycosylation in the virulence of this fungus, we deleted the Golgi P-type ATPase, which transports divalent cations into the Golgi, where they act as essential cofactors for mannosyltransferases. In Saccharomyces cerevisiae, glycosylation is initiated in the endoplasmic reticulum by the transfer of the first mannose residue to serine or threonine in O-linked glycosylation (13Strahl-Bolsinger S. Gentzsch M. Tanner W. Biochim. Biophys. Acta. 1999; 1426: 297-307Crossref PubMed Scopus (256) Google Scholar) and by the transfer of the N-linked core structure to asparagine residues (14Knauer R. Lehle L. Biochim. Biophys. Acta. 1999; 1426: 259-273Crossref PubMed Scopus (171) Google Scholar). The construction and transfer of the N-linked core (14Knauer R. Lehle L. Biochim. Biophys. Acta. 1999; 1426: 259-273Crossref PubMed Scopus (171) Google Scholar, 15Burda P. Aebi M. Biochim. Biophys. Acta. 1999; 1426: 239-257Crossref PubMed Scopus (529) Google Scholar) and the initiation of O-linked glycosylation (16Gentzsch M. Tanner W. EMBO J. 1996; 15: 5752-5759Crossref PubMed Scopus (220) Google Scholar) are essential processes. Glycosylation is continued in the Golgi with the extension of the linear O-linked glycans (17Lussier M. Sdicu A.M. Bussey H. Biochim. Biophys. Acta. 1999; 1426: 323-334Crossref PubMed Scopus (123) Google Scholar) and the extensive elaboration of the branched outer chains of the N-linked glycans (18Dean N. Biochim. Biophys. Acta. 1999; 1426: 309-322Crossref PubMed Scopus (158) Google Scholar). The process of glycosylation has been extensively studied in S. cerevisiae (13Strahl-Bolsinger S. Gentzsch M. Tanner W. Biochim. Biophys. Acta. 1999; 1426: 297-307Crossref PubMed Scopus (256) Google Scholar, 14Knauer R. Lehle L. Biochim. Biophys. Acta. 1999; 1426: 259-273Crossref PubMed Scopus (171) Google Scholar, 15Burda P. Aebi M. Biochim. Biophys. Acta. 1999; 1426: 239-257Crossref PubMed Scopus (529) Google Scholar, 17Lussier M. Sdicu A.M. Bussey H. Biochim. Biophys. Acta. 1999; 1426: 323-334Crossref PubMed Scopus (123) Google Scholar), and this has provided a resource for understanding glycosylation in C. albicans. However, key differences exist between the O- and N-glycan structures present in S. cerevisiae and C. albicans. For example, in C. albicans, the terminal O-linked glycans that are attached by α1,2-linkages, as opposed to α1,3-linkages in S. cerevisiae (19Munro C.A. Bates S. Buurman E.T. Hughes H.B. MacCallum D.M. Bertram G. Atrih A. Ferguson M.A. Bain J.M. Brand A. Hamilton S. Westwater C. Thomson L.M. Brown A.J.P. Odds F.C. Gow N.A.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and mannose residues are present in the and N-linked glycans N. M. M. H. S. Infect. Immun. 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To the the and of the by and with the and and and with the and and into the of 1993; PubMed Google Scholar). The was by with and and the by and of CaPMR1. was disrupted by of of and the of the by on acid and To with the of A. MacCallum D.M. Brown A.J.P. Gow N.A.R. Odds F.C. Cell. PubMed Scopus Google Scholar), the null was with A.M. Lee Brown A.J.P. 2000; PubMed Google Scholar) that was the to as To a to act as a the of and of by and and the was into The was by and into the of The was with and into the null a for was also with in this have the The in by the of a in the or of an of an to have into the for to grown for in and then with and These cells into and into in a of for and was in The Calcofluor Congo hygromycin B a or and The are the for was by for for of 2nd Ed. for Scholar), that the of the C. albicans are to highly to and for activation of the cell integrity H. C. H. W. S. M. 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The of is to a protein of the C. albicans has been this to as the of S. cerevisiae in S. cerevisiae, is to which is involved in However, the of the is and the of in the The acid of demonstrated to secretory P-type of and to Pmr1p of S. cerevisiae, and and and are by and by the of this to P-type with P-type the are into by a that the P-type ATPase R. Biochim. Biophys. Acta. PubMed Scopus Google Scholar) are in In the acid residue in the that is the in P-type A. G. R. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). the to important in the the and responsible for are also of was disrupted in by the 1993; PubMed Google Scholar). This involved the of the containing of P-type To with of the with that was the A. MacCallum D.M. Brown A.J.P. Gow N.A.R. Odds F.C. Cell. PubMed Scopus Google Scholar, A.M. Lee Brown A.J.P. 2000; PubMed Google Scholar). A was also in which was the of into the Capmr1Δ null mutant the with was as a in of had no effect on growth in or However, the cells in to was also no defect in in to or However, was a in on Both the and the in on to of the in the in vitro growth was in the Capmr1Δ null mutant. in of had no effect on the growth of the in ions are present in media and growth the Capmr1Δ mutant was grown in was no effect on growth The of Ca2+ in this was the of and However, viable cell was that the null mutant to viability as the cells stationary phase. of growth in the viability of the null mutant by the null mutant was grown in was also a in viability of viability was the was grown in with The and no of viability grown on of the Ca2+ The Capmr1Δ null mutant was also to of the null mutant was completely by the of the and This hypersensitivity by the of Ca2+ or by an of in S. cerevisiae, of to the or the of Glycosylation in the Capmr1Δ the Golgi with ions that are as a for the mannosyltransferases. therefore the of and O-linked glycosylation in the Capmr1Δ null mutant. the of acid which is to by F.C. J. PubMed Google Scholar). The of acid present in protein the Capmr1Δ null mutant was on the the null mutant had an with to the N-linked the acid through the still as a to in O-linked In this was no the null mutant and and However, O-linked chains are this to glycosylated chains the which is as the protein passes through the Golgi. This the cell wall with and with the The Capmr1Δ null mutant demonstrated a in in the to in the null mutant of the The had an of of the also the by with and was by of cell The demonstrated that the Capmr1Δ null mutant was almost completely of The and of to mannose residues C.A. Bates S. MacCallum D.M. J.E. Brown Odds F.C. Gow N.A.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, G. G. D. 1997; PubMed Scopus Google Scholar). The of of on the O-mannan structure was also by of C. albicans to mannose the first is in the endoplasmic and residues are in the Golgi. The demonstrated that O-mannan was truncated in the Capmr1Δ null mutant with almost no to The that was present on the O-mannan that was in the Capmr1Δ null mutant. of to the null mutant the O-mannan To the gross glycosylation defect in the Capmr1Δ null mutant and to determine the effect on the cell wall, we wall by with This the carbohydrate of the wall by where and are These to the of and in the cell wall, This demonstrated a defect in which of the cell wall in the to in the Capmr1Δ null mutant This was with an increase in in the to in the null mutant. The of in the was and determine the effect of on the integrity of the cell wall, we the null mutant for to a of cell and have been with cell and The Capmr1Δ null mutant was to the cell Calcofluor and Congo and to hygromycin B a in glycosylation N. S. A. PubMed Scopus Google Scholar). However, was no in the of to as and demonstrated that the null mutant no in to in the and and the The hypersensitivity of the Capmr1Δ null mutant to cell that the wall is and is to we the cell integrity was in the mutant. The cell integrity through and results in the of the H. C. H. W. S. M. F.M. 2000; PubMed Scopus Google Scholar). the activation of in our by with a that to was in the Capmr1Δ null mutant was in the and a the also with Calcofluor for This demonstrated activation of the cell integrity pathway. The results of and the constitutive activation of the cell wall integrity that the Capmr1Δ null mutant has a cell of the Capmr1Δ have been implicated in C. albicans we the of the Capmr1Δ mutant to to that was an increase in in the with in the null mutant. However, the null mutant as of cells and this increase in the null mutant the of with or cells increase for the and for the null that was The Capmr1Δ in virulence of the Capmr1Δ null mutant and was in a model of systemic The Capmr1Δ null mutant was highly attenuated in with the of the with the demonstrated a of and The demonstrated an with a of which was with the null mutant The is of a effect on virulence. are of and containing a of the J. Cell. 2003; PubMed Scopus Google Scholar, P. Microbiol. PubMed Scopus Google Scholar, J.H. Microbiol. 2003; PubMed Scopus Google Scholar). In of for and of the and The Capmr1Δ null mutant demonstrated a in with a in and a in also a of of and of with the Capmr1Δ mutant. although the Capmr1Δ mutant was in growth in this null mutant was attenuated in virulence in a and for with the Capmr1Δ null mutant and in a In this we have the effect of a gross defect in glycosylation in C. albicans by a null mutant in which is for glycosylation in the Golgi. Pmr1p is a P-type ATPase and the Golgi with and In the Golgi, ions are as an essential for mannosyltransferases. by we determine the effect of a defect in glycosylation the and in The Capmr1Δ null mutant demonstrated a glycosylation defect and cell wall and was severely attenuated in virulence in a murine model of systemic have also gross glycosylation by the S. N. A. Microbiol. 2000; PubMed Scopus Google Scholar) and A. Y. N. J. 2002; PubMed Scopus Google Scholar) of into the Golgi, where as the mannose for mannosyltransferases. of would glycosylation in the Golgi, also the essential of and of the in the endoplasmic as these require which is which was to and was to have S. N. A. Microbiol. 2000; PubMed Scopus Google Scholar). The Golgi is essential in C. albicans A. Y. N. J. 2002; PubMed Scopus Google Scholar) and S. cerevisiae N. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, C. N. PubMed Google Scholar). This that a of glycosylation in the Golgi results in The essential of and the importance of that the role of the glycans in host-fungus interactions and virulence The Golgi has also been studied D. A. C. Cell. 2002; 1: PubMed Scopus Google this to which is then the Golgi by in an process with However, is to and a gross glycosylation It demonstrate a defect in and, as by has a in no defect in the In S. cerevisiae, of PMR1 results in a a growth which by ions to the Ca2+ in the in the viability upon entering stationary A. J. Cell. Full Text PDF PubMed Scopus Google Scholar). In our of had no effect on the growth of the even grown on the viability was of that in S. cerevisiae, in that the Capmr1Δ null mutant lost viability upon entering stationary growth on differences in the of ions in S. cerevisiae and C. albicans. in S. cerevisiae, we also no in the of to the Capmr1Δ null mutant. are also differences in the of S. cerevisiae and C. albicans to The in viability of the null mutant entering stationary ions are present in of which is in an A. P.G. J. PubMed Scopus Google Scholar). This that present in where a in viability was although we that this have the virulence is to a effect and ion and, as for the almost of virulence in the Capmr1Δ mutant. in Y. has that of Pmr1p on the protein is or Lee J. 1998; PubMed Google Scholar). of Pmr1p also the of proteins in S. cerevisiae and K. PubMed Scopus Google Scholar, J. Microbiol. 1996; PubMed Scopus Google Scholar, D. P. C. J. PubMed Scopus Google Scholar). the of in the Capmr1Δ null mutant by the of acid and a in the of acid of the and a increase in the of of the the in in the Capmr1Δ null mutant as as in However, was these that the of are on the protein that is we that proteins acid and severely in the Capmr1Δ null mutant. The Capmr1Δ null mutant had a with most cells present in This to in the cell wall in However, of the that they the of a cell This that cells are in cell wall to a in the of cell A has been for C. albicans glycosylation as the mutant (19Munro C.A. Bates S. Buurman E.T. Hughes H.B. MacCallum D.M. Bertram G. Atrih A. Ferguson M.A. Bain J.M. Brand A. Hamilton S. Westwater C. Thomson L.M. Brown A.J.P. Odds F.C. Gow N.A.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). A was in the and C.A. C. J. J. 1999; PubMed Google Scholar, A. Y. N. J. 2002; PubMed Scopus Google Scholar). A defect in an S. mutant has also been R. K. J. Cell. PubMed Scopus Google Scholar). The with in vitro of However, was that the of epithelial cells to was in the that of Pmr1p have a effect on was for a gross defect in glycosylation in the Capmr1Δ null with severely as demonstrated by the of acid and the almost of was also that O-mannan was truncated with a in to The that was still present in O-mannan the Capmr1Δ null mutant that mannosyltransferases are still in the Golgi. This the of mannosyltransferases the Golgi, where of the the endoplasmic in the Capmr1Δ null have been present was in an Golgi that ions endoplasmic This also that which is almost completely in the Capmr1Δ null is a in the Golgi and, as is to the of the of in the O-mannan of the Capmr1Δ null mutant the of mannosyltransferases for that have the most in a The cell wall was in the Capmr1Δ null exemplified by the in mannose with the gross glycosylation The of the of Pmr1p to in the constitutive activation of the cell integrity to for the of The null mutant was to the cell Calcofluor and Congo red, which and and with and to hygromycin a of in S. cerevisiae N. S. A. PubMed Scopus Google Scholar), was also However, we no in to to which is with in S. cerevisiae C. N. PubMed Google Scholar, L. R.A. S. A. PubMed Scopus Google Scholar). was also no in to which would cell wall proteins and the or to that the mutant was The Capmr1Δ null mutant no growth defect in had an cell wall to the gross glycosylation This to the importance to virulence of glycosylation that in the Golgi. The null mutant was highly attenuated in with the of the and a in The low and the of that the host was to or that the mutant was to These results the importance of glycosylation to the cell wall and the of C. albicans still the of epitopes involved in in of carbohydrate has the importance of (19Munro C.A. Bates S. Buurman E.T. Hughes H.B. MacCallum D.M. Bertram G. Atrih A. Ferguson M.A. Bain J.M. Brand A. Hamilton S. Westwater C. Thomson L.M. Brown A.J.P. Odds F.C. Gow N.A.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and the importance of C.A. Bates S. MacCallum D.M. J.E. Brown Odds F.C. Gow N.A.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). into the and of epitopes to these and for with the cell wall and for with acid