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Adhesins in Human Fungal Pathogens: Glue with Plenty of Stick

Piet W. J. de Groot, Oliver Bader, Albert D. de Boer, Michael Weig, Neeraj Chauhan
Piet W. J. de Groot
aRegional Center for Biomedical Research, Albacete Science and Technology Park, University of Castilla—La Mancha, Albacete, Spain
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Oliver Bader
bInstitute for Medical Microbiology and German National Reference Center for Systemic Mycoses, University Medical Center Göttingen, Göttingen, Germany
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Albert D. de Boer
aRegional Center for Biomedical Research, Albacete Science and Technology Park, University of Castilla—La Mancha, Albacete, Spain
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Michael Weig
bInstitute for Medical Microbiology and German National Reference Center for Systemic Mycoses, University Medical Center Göttingen, Göttingen, Germany
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Neeraj Chauhan
cPublic Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
dDepartment of Microbiology and Molecular Genetics, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
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DOI: 10.1128/EC.00364-12
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    Fig 1

    Generic structure and posttranslational processing steps leading to cell wall incorporation of fungal adhesins. Abundant protein N- and O-glycosylation, the latter especially taking place in the low-complexity domain, is not depicted for simplicity reasons. EtN-P, ethanolamine phosphate; Glc, glucose; GlcN, glucosamine; Man, mannose; PM, plasma membrane; PI, phosphatidylinositol.

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    Fig 2

    The C. albicans Hwp1 and Iff/Hyr families contain family-specific repeat sequences. (A) Diagram showing modular structures of the protein precursors of the Hwp1 family. Included are all 12 C. albicans SC5314 proteins (genome assembly 21) containing at least one copy of the pattern T[ILV][ST]XCX(4)CX(16,20)TX[VYF][TV]T[YF]CP[ILV] (PROSITE format), which are indicated as diagonally striped boxes. N-terminal high-complexity domains of the mature proteins, believed to comprise effector domains, are presented in different colors because of their lack of sequence similarity. The two EAP1 alleles in strain SC5314 differ in length at a region that predominantly encodes repeats of a “PATEST” pattern (indicated by vertically striped boxes). A region with imperfect 41-to-50-aa serine-rich repeats in Pga18 is shown as the boxes with the thinner diagonal stripes. Signal peptides (SP) for ER entry and GPI anchoring are indicated. Putative and experimentally validated proteolytic Kex2 cleavage sites are depicted by open and black triangles, respectively. (B and C) Sequence logos (created at http://weblogo.berkeley.edu/) of the Hwp1 group (B) and of the Iff/Hyr family repeats (75) (C). Amino acid color codes for both panels are as follows: purple, conserved tryptophan in the Iff group, cysteines, and prolines; green, amyloid forming (TLVIA); red, positively charged (KRH); blue, negatively charged (DE); orange, all other amino acids. Alignments used for building the logos have been communicated to Pfam (http://pfam.janelia.org/) for creation of Pfam hidden Markov models (HMM) entries. All Iff/Hyr repeats from reference 75 match the pattern WX(2)TX (7)TX(2)G[IV](2).

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    Fig 3

    Genomic organization of putative adhesin-encoding genes in the sequenced C. glabrata strain CBS138, modified from reference 8. Chromosomes and open reading frames (ORFs) are numbered following Génolevures's systematic ORF numbering, which is also used in the Candida Genome Database. ORF sizes are to scale, but distances between ORFs are not. Many of the gene sequences, when translated, give rise to frameshifts, probably mostly due to sequencing and/or annotation errors or the presence of intronic sequences. Some unannotated ORF fragments (no ORF number), identified by BLASTX, are connected to incomplete ORFs. Colors indicate seven subfamilies, sharing homology in the N-terminal putative ligand-binding parts. Numbers of genes in each group are indicated. N-terminal domains of CAGL0L09911g and CAGL0J05170g (white) are unrelated to the other adhesins. For CAGL0E00187g (group IV, pink), only the GPI anchor peptide containing the C-terminal part was identified; its classification is therefore based on BLASTP analysis of this region. Numbers of nonadhesin ORFs separating adhesin-like ORFs and telomeres and distances of terminal adhesin-like genes to the end of the obtained telomeric DNA sequences are indicated. Numbers of the megasatellite signatures [VILF][VI][ST]H[IVS][TI][TGI] (“VVSHITT”) and SFFIT are specified only for ORFs whose protein sequences are complete in the databases. Arrows indicate directions of transcription.

Tables

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  • Table 1

    Adhesins in C. albicans

    Protein name(s)aStructural propertiesbSubstrate and/or functional propertiescReference(s)
    Als familyd21
        Als11,260 aa; contains amyloid-forming sequencesEndothelial and epithelial cells; fibronectin-, laminin-, and fucose-containing glycans; abiotic surfaces such as glass and plastics; cell-cell interaction; biofilm induced; contributes to biofilm formation and pathogenesis32, 34–36, 37, 38, 39–41, 42
        Als2∼2,531 aa (Als2 in CGD is incomplete; length inferred from comparison to Als2 in strain 1161 (GenBank accession no. AAC64236)Endothelial cells; abiotic surfaces such as glass and plastics; contributes to biofilm formation and pathogenesis35, 36, 37
        Als31,155 aa; contains amyloid-forming sequencesEndothelial and epithelial cells; fibronectin, laminin, saliva-coated particles, and type IV collagen; abiotic surfaces such as glass and plastics; Streptococcus gordonii and Staphylococcus aureus; cell-cell interaction; transferrin receptor in iron acquisition; invasin; induction of C. albicans endocytosis; host cell damage; contributes to biofilm formation and pathogenesis; hypha specific26, 35, 43, 37, 41, 44–47, 48, 49
        Als42,100 aaEndothelial cells; abiotic surfaces such as glass and plastics; functional overlap with Als236, 37
        Als51,347 aa; contains amyloid-forming sequencesExtracellular matrix proteins; abiotic surfaces such as such as glass and plastics; deletion mutant more adherent to endothelial and epithelial cells; aggregation; contributes to biofilm formation and pathogenesis50, 43, 37, 51, 52–54
        Als61,366 aaGelatin; abiotic surfaces such as glass and plastics; deletion mutant more adherent to endothelial and epithelial cells43, 37, 54
        Als71,568 aa; copy numbers of TR units are highly variableAbiotic surfaces such as glass and plastics; deletion mutant more adherent to endothelial and epithelial cells43, 37, 54, 55
        Als91,890 aa; allelic diversity; N-terminal ligand binding (Als9-2)Endothelial cells (N-terminal Als9-2); laminin; abiotic surfaces such as glass and plastics32, 37, 54
    Hwp1 familye41, 56
        Hwp1634 aa; glutamine-rich N-terminal domain serves as host transglutaminase substrate; putative site for proteolytic processing; 2 Hwp1 repeatsSaliva- or fibronectin-coated surfaces; buccal epithelial cells displaying keratin 13 and SRP3; polystyrene, but less binding to silicone; low attachment to Streptococcus gordonii; role in biofilm formation; hypha specific; Tup1 repressed26, 40, 57–60
        Hwp2/Pga8908 aa; short N-terminal high-complexity region; putative site for proteolytic processing; 2 Hwp1 repeatsEpithelial cells; polystyrene; role in biofilm formation on silicone; expressed in hyphae61, 57, 62, 63
        Rbt1721/714 aa; N-terminal high-complexity region; putative sites for proteolytic processing; propeptide found in growth medium; 2 Hwp1 repeatsSerum; hypha induced; Tup1 repressed; required for full virulence57, 64, 63, 65
        Eap1/Pga47653/1,121 aa; alleles differ in number of 6-aa repeats; short N-terminal high-complexity region; putative site for proteolytic processing; 2 Hwp1 repeatsEpithelial cells; Streptococcus gordonii; polystyrene; role in biofilm formation, filamentation, and mating26, 66, 67–70
        Ywp1/Pga24533 aa; N-terminal high-complexity region; 2 sites for proteolytic processing; propeptide found in growth medium; Sap9 cleaved; 2 Hwp1 repeatsMutant shows increased adhesion and biofilm formation; expressed in yeast cells71, 56
    Iff/Hyr familyf
        Hyr1919 aaMediates resistance to neutrophil killing; anti-Hyr1 AB is immunoprotective; hypha specific; Bcr1 dependent40, 72, 73, 74
        Rbr3/Iff11,562 aa; 10 Iff/Hyr repeats; 2 putative sites for proteolytic processingUpregulated at low pH; expression is repressed by Rim101 and activated by Nrg175, 76
        Hyr3/Iff21,249 aa; 4 Iff/Hyr repeats; putative proteolytic-processing site75
        Iff3941 aa; 2 Iff/Hyr repeats; putative site for proteolytic processing75
        Iff41.526 aaEpithelial cells; plastics; implicated in virulence77–79
        Iff51,308 aa; 5 Iff/Hyr repeats75
        Iff61,086 aa; putative site for proteolytic processing
        Hyr4/Iff71,225 aa; 3 Iff/Hyr repeats75
        Iff8714 aa
        Iff9940 aa; 2 Iff/Hyr repeats75
        Flo9/Iff101,244 aa
        Iff11511 aa; no GPI anchor peptide; secreted proteinRequired for normal cell wall structure and virulence80
    • ↵a Protein names are from the Candida Genome Database (CGD) (http://www.candidagenome.org/).

    • ↵b All listed proteins contain signal peptides for ER entry; all except Iff11 contain C-terminal signals for GPI anchoring.

    • ↵c Only the most relevant phenotypes are listed.

    • ↵d Als family proteins share similar domain structures with N-terminal effector domains that are 55 to 90% identical across the whole family, central domains with tandem repeats (TR), and variable Ser/Thr-rich C-terminal domains.

    • ↵e Hwp1 family proteins have in common the presence of one or more Hwp1 repeats.

    • ↵f Iff/Hyr family proteins share a protein structure with a conserved putative N-terminal effector domain followed by a low-complexity C-terminal domain. The latter may contain a variable number of Iff/Hyr repeats.

  • Table 2

    Adhesins in non-Candida human pathogenic fungi

    FungusAdhesin (accession no.)Structural propertiesaSubstrate and/or functional propertiesReference(s)
    Aspergillus fumigatusRodA (EAL91643.1)159 aa, GPI?Hydrophobin; adhesion to collagen and bovine serum albumin93, 94
    CalA (EAL92612.1)177 aaBinding to laminin and murine lung cells95
    CspA (XP_754717.1)430 aa, repeats, GPIConidial adhesion to ECM of human alveolar epithelial cells; expression during conidial germination96
    Cryptococcus neoformansCfl1 (AFR92926.1)309 aaCell-cell adhesion (flocculation); biofilm formation; hypha specific97
    Coccidioides immitisSOWgp (AAL09436.1)422 aa, repeats, GPIBinding to laminin, fibronectin, and collagen IV; role in virulence; spherule outer wall protein98
    Blastomyces dermatitidisBAD1/WI-1 (AAA91036.1)1,146 aa, repeats, epidermal growth factor-like cysteine-rich consensus sequence at C terminusAdhesion to yeast chitin and macrophages; modulation of TNF-α production by phagocytes99, 100
    • ↵a All proteins have signal peptides for secretion. GPI, glycosylphosphatidylinositol-anchoring signal peptide. The GPI-anchor signal prediction in RodA is controversial as it includes one of the eight cysteines, which are believed to be crucial for correct folding of this amphipathic protein.

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Adhesins in Human Fungal Pathogens: Glue with Plenty of Stick
Piet W. J. de Groot, Oliver Bader, Albert D. de Boer, Michael Weig, Neeraj Chauhan
Eukaryotic Cell Mar 2013, 12 (4) 470-481; DOI: 10.1128/EC.00364-12

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Adhesins in Human Fungal Pathogens: Glue with Plenty of Stick
Piet W. J. de Groot, Oliver Bader, Albert D. de Boer, Michael Weig, Neeraj Chauhan
Eukaryotic Cell Mar 2013, 12 (4) 470-481; DOI: 10.1128/EC.00364-12
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  • Top
  • Article
    • ABSTRACT
    • INTRODUCTION
    • ADHESINS ARE OUTER-SURFACE COMPONENTS OF THE FUNGAL CELL WALL
    • CANDIDA ALBICANS ADHESINS
    • ADHESINS IN NON-ALBICANS CTG-CLADE CANDIDA SPECIES
    • CANDIDA GLABRATA ADHESINS
    • ASPERGILLUS FUMIGATUS ADHESINS
    • CRYPTOCOCCUS NEOFORMANS ADHESINS
    • ADHESINS IN FUNGI CAUSING ENDEMIC MYCOSES AND RARE FUNGAL DISEASES
    • SUMMARY
    • ACKNOWLEDGMENTS
    • REFERENCES
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