title: Enteric pathogens deploy cell cycle inhibiting factors to block the bactericidal activity of Perforin-2.
abstract: Perforin-2 (MPEG1) is an effector of the innate immune system that limits the proliferation and spread of medically relevant Gram-negative, -positive, and acid fast bacteria. We show here that a cullin-RING E3 ubiquitin ligase (CRL) complex containing cullin-1 and βTrCP monoubiquitylates Perforin-2 in response to pathogen associated molecular patterns such as LPS. Ubiquitylation triggers a rapid redistribution of Perforin-2 and is essential for its bactericidal activity. Enteric pathogens such as Yersinia pseudotuberculosis and enteropathogenic Escherichia coli disarm host cells by injecting cell cycle inhibiting factors (Cifs) into mammalian cells to deamidate the ubiquitin-like protein NEDD8. Because CRL activity is dependent upon NEDD8, Cif blocks ubiquitin dependent trafficking of Perforin-2 and thus, its bactericidal activity. Collectively, these studies further underscore the biological significance of Perforin-2 and elucidate critical molecular events that culminate in Perforin-2-dependent killing of both intracellular and extracellular, cell-adherent bacteria.
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: McCormack
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States.
authors.forename: Kirill
authors.initials: K
authors.lastname: Lyapichev
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Olsson
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States.
authors.forename: Eckhard R
authors.initials: ER
authors.lastname: Podack
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States.
authors.forename: George P
authors.identifier: http://orcid.org/0000-0002-3692-8199
authors.initials: GP
authors.lastname: Munson
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism; D054308:Enteropathogenic Escherichia coli / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D050296:Microbial Viability; D000075687:NEDD8 Protein; D052899:Pore Forming Cytotoxic Proteins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D014452:Ubiquitins / Q000037:antagonists & inhibitors; D037521:Virulence Factors / Q000378:metabolism*; D015011:Yersinia pseudotuberculosis / Q000276:immunology* / Q000502:physiology
chemical_list: D044842:Cullin Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D052899:Pore Forming Cytotoxic Proteins; D014452:Ubiquitins; D037521:Virulence Factors; C510469:perforin 2
keywords: Cif; E. coli; EPEC; MPEG1; NEDD8; Perforin-2; Yersinia pseudotuberculosis; human; immunology; infectious disease; microbiology; mouse