title: IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection.
abstract: Inflammasomes are cytoplasmic sensors of foreign molecules, including pathogens, and function to induce caspase-1 activation and IL-1β cytokine maturation. Whether such a mechanism exists in the nucleus and is effective against nuclear replicating pathogens is unknown. Nuclear replicating herpesvirus KSHV is associated with Kaposi Sarcoma, an angioproliferative tumor characterized by an inflammatory microenvironment including IL-1β. We demonstrate that during KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome. This complex was initially detected in the nucleus and subsequently in the perinuclear area. KSHV gene expression and/or latent KSHV genome is required for inflammasome activation and IFI16 colocalizes with the KSHV genome in the infected cell nucleus. Caspase-1 activation by KSHV was reduced by IFI16 and ASC silencing. Our studies reveal IFI16 as a nuclear pathogen sensor and demonstrate that the inflammasome also functions in the nucleus.
authors.affiliation: H.M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA. bala.chandran@rosalindfranklin.edu
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Kerur
authors.forename: Mohanan Valiya
authors.initials: MV
authors.lastname: Veettil
authors.forename: Neelam
authors.initials: N
authors.lastname: Sharma-Walia
authors.forename: Virginie
authors.initials: V
authors.lastname: Bottero
authors.forename: Sathish
authors.initials: S
authors.lastname: Sadagopan
authors.forename: Pushpalatha
authors.initials: P
authors.lastname: Otageri
authors.forename: Bala
authors.initials: B
authors.lastname: Chandran
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology / Q000821:virology; D019288:Herpesvirus 8, Human / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000096:biosynthesis* / Q000276:immunology*; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping
chemical_list: D058847:Inflammasomes; D009687:Nuclear Proteins; D010750:Phosphoproteins; C076700:IFI16 protein, human