title: Caspase-1 cleavage of the TLR adaptor TRIF inhibits autophagy and β-interferon production during Pseudomonas aeruginosa infection.
abstract: Bacterial infection can trigger autophagy and inflammasome activation, but the effects of inflammasome activation on autophagy are unknown. We examined this in the context of Pseudomonas aeruginosa macrophage infection, which triggers NLRC4 inflammasome activation. P. aeruginosa induced autophagy via TLR4 and its adaptor TRIF. NLRC4 and caspase-1 activation following infection attenuated autophagy. Caspase-1 directly cleaved TRIF to diminish TRIF-mediated signaling, resulting in inhibition of autophagy and in reduced type I interferon production. Expression of a caspase-1 resistant TRIF mutant enhanced autophagy and type I interferon production following infection. Preventing TRIF cleavage by caspase-1 in an in vivo model of P. aeruginosa infection resulted in enhanced bacterial autophagy, attenuated IL-1β production, and increased bacterial clearance. Additionally, TRIF cleavage by caspase-1 diminished NLRP3 inflammasome activation. Thus, caspase-1 mediated TRIF cleavage is a key event in controlling autophagy, type I interferon production, and inflammasome activation with important functional consequences.
authors: Institute of Immunity, Infection and Inflammation, University of Glasgow, Glasgow G12 8TA, UK; University of Technology, Applied Science School, Biotechnology Department, Baghdad, Iraq.
authors: Majid Sakhi
authors: MS
authors: Jabir
authors: Institute of Immunity, Infection and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors: Neil D
authors: ND
authors: Ritchie
authors: Institute of Immunity, Infection and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors: Dong
authors: D
authors: Li
authors: Institute of Immunity, Infection and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
authors: Hannah K
authors: HK
authors: Bayes
authors: Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES UK.
authors: Panagiotis
authors: P
authors: Tourlomousis
authors: Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors: Daniel
authors: D
authors: Puleston
authors: Department of Pathology, Western Infirmary, Glasgow G11 6NT, UK.
authors: Alison
authors: A
authors: Lupton
authors: Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES UK.
authors: Lee
authors: L
authors: Hopkins
authors: Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors: Anna Katharina
authors: AK
authors: Simon
authors: Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES UK.
authors: Clare
authors: C
authors: Bryant
authors: Institute of Immunity, Infection and Inflammation, University of Glasgow, Glasgow G12 8TA, UK. Electronic address: tom.evans@glasgow.ac.uk.
authors: Thomas J
authors: TJ
authors: Evans
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D001343:Autophagy; D002135:Calcium-Binding Proteins / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D006868:Hydrolysis; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C512299:Ipaf protein, mouse; C470409:TICAM1 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D020170:Caspase 1