title: The Chlamydia protease CPAF regulates host and bacterial proteins to maintain pathogen vacuole integrity and promote virulence.
abstract: The obligate intracellular bacterial pathogen Chlamydia trachomatis injects numerous effector proteins into the epithelial cell cytoplasm to manipulate host functions important for bacterial survival. In addition, the bacterium secretes a serine protease, chlamydial protease-like activity factor (CPAF). Although several CPAF targets are reported, the significance of CPAF-mediated proteolysis is unclear due to the lack of specific CPAF inhibitors and the diversity of host targets. We report that CPAF also targets chlamydial effectors secreted early during the establishment of the pathogen-containing vacuole ("inclusion"). We designed a cell-permeable CPAF-specific inhibitory peptide and used it to determine that CPAF prevents superinfection by degrading early Chlamydia effectors translocated during entry into a preinfected cell. Prolonged CPAF inhibition leads to loss of inclusion integrity and caspase-1-dependent death of infected epithelial cells. Thus, CPAF functions in niche protection, inclusion integrity and pathogen survival, making the development of CPAF-specific protease inhibitors an attractive antichlamydial therapeutic strategy.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ine
authors.initials: I
authors.lastname: Jorgensen
authors.forename: Maria M
authors.initials: MM
authors.lastname: Bednar
authors.forename: Vishar
authors.initials: V
authors.lastname: Amin
authors.forename: Beckley K
authors.initials: BK
authors.lastname: Davis
authors.forename: Jenny P Y
authors.initials: JP
authors.lastname: Ting
authors.forename: Dewey G
authors.initials: DG
authors.lastname: McCafferty
authors.forename: Raphael H
authors.initials: RH
authors.lastname: Valdivia
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D058947:Bacterial Secretion Systems; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002463:Cell Membrane Permeability; D002692:Chlamydia trachomatis / Q000378:metabolism / Q000472:pathogenicity*; D010450:Endopeptidases / Q000378:metabolism*; D004847:Epithelial Cells / Q000382:microbiology; D054884:Host-Pathogen Interactions; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; C550863:CT694 protein, Chlamydia trachomatis; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D010455:Peptides; D011480:Protease Inhibitors; D037521:Virulence Factors; D010450:Endopeptidases; D020170:Caspase 1; C425923:CPA factor