title: Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-γ.
abstract: Innate immune sensors such as Toll-like receptors (TLRs) differentially utilize adaptor proteins and additional molecular mediators to ensure robust and precise immune responses to pathogen challenge. Through a gain-of-function genetic screen, we identified the gamma catalytic subunit of protein phosphatase 1 (PP1-γ) as a positive regulator of MyD88-dependent proinflammatory innate immune activation. PP1-γ physically interacts with the E3 ubiquitin ligase TRAF6, and enhances the activity of TRAF6 towards itself and substrates such as IKKγ, whereas enzymatically inactive PP1-γ represses these events. Importantly, these activities were found to be critical for cellular innate responses to pathogen challenge and microbial clearance in both mouse macrophages and human monocyte lines. These data indicate that PP1-γ phosphatase activity regulates overall TRAF6 E3 ubiquitin ligase function and promotes NF-κB-mediated innate signaling responses.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Opaluch
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Monika
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Chih-yuan
authors.initials: CY
authors.lastname: Chiang
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Quy T
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: Department of Microbiology and The Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Maestre
authors.affiliation: Department of Microbiology and The Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Lubbertus C F
authors.initials: LC
authors.lastname: Mulder
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ismael
authors.initials: I
authors.lastname: Secundino
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Paul D
authors.initials: PD
authors.lastname: De Jesus
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America ; Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Research Group "Host-Pathogen Interactions", Langen, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: König
authors.affiliation: Department of Microbiology and The Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Viviana
authors.initials: V
authors.lastname: Simon
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Graham
authors.initials: G
authors.lastname: MacLeod
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Susannah
authors.initials: S
authors.lastname: Varmuza
authors.affiliation: Department of Microbiology and The Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007113:Immunity, Innate; D047468:Immunoprecipitation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D013291:Streptococcus / Q000472:pathogenicity; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; C517103:Ppp1cc protein, mouse; D054645:Protein Phosphatase 1