Abstract
Cif (PA2934), a bacterial virulence factor secreted in outer membrane vesicles by Pseudomonas aeruginosa, increases the ubiquitination and lysosomal degradation of some, but not all, plasma membrane ATP-binding cassette transporters (ABC), including the cystic fibrosis transmembrane conductance regulator and P-glycoprotein. The goal of this study was to determine whether Cif enhances the ubiquitination and degradation of the transporter associated with antigen processing (TAP1 and TAP2), members of the ABC transporter family that play an essential role in antigen presentation and intracellular pathogen clearance. Cif selectively increased the amount of ubiquitinated TAP1 and increased its degradation in the proteasome of human airway epithelial cells. This effect of Cif was mediated by reducing USP10 deubiquitinating activity, resulting in increased polyubiquitination and proteasomal degradation of TAP1. The reduction in TAP1 abundance decreased peptide antigen translocation into the endoplasmic reticulum, an effect that resulted in reduced antigen available to MHC class I molecules for presentation at the plasma membrane of airway epithelial cells and recognition by CD8(+) T cells. Cif is the first bacterial factor identified that inhibits TAP function and MHC class I antigen presentation.
Keywords:
ABC Transporter; Airway Epithelial Cell; Antigen Processing; Deubiquitination; Pseudomonas aeruginosa; TAP; Ubiquitination; Viral-Bacterial Co-infection.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / immunology
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ATP-Binding Cassette Transporters / metabolism*
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Antigen Presentation*
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Bacterial Proteins / genetics
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Bacterial Proteins / immunology
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Bacterial Proteins / metabolism*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Endoplasmic Reticulum / genetics
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Endoplasmic Reticulum / immunology
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Endoplasmic Reticulum / metabolism
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / immunology
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Histocompatibility Antigens Class I / metabolism*
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / immunology
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Proteasome Endopeptidase Complex / metabolism*
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Protein Transport / genetics
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Protein Transport / immunology
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Pseudomonas aeruginosa / genetics
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Pseudomonas aeruginosa / immunology
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Pseudomonas aeruginosa / metabolism*
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Pseudomonas aeruginosa / pathogenicity
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Ubiquitin Thiolesterase / genetics
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Ubiquitin Thiolesterase / immunology
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Ubiquitin Thiolesterase / metabolism
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Ubiquitination*
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Virulence Factors / genetics
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Virulence Factors / immunology
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Virulence Factors / metabolism*
Substances
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ATP-Binding Cassette Transporters
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Bacterial Proteins
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Cif protein, Pseudomonas aeruginosa
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Histocompatibility Antigens Class I
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USP10 protein, human
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Virulence Factors
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transporter associated with antigen processing (TAP)
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Ubiquitin Thiolesterase
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Proteasome Endopeptidase Complex