title: Interferon-inducible p200-family protein IFI16, an innate immune sensor for cytosolic and nuclear double-stranded DNA: regulation of subcellular localization.
abstract: The interferon (IFN)-inducible p200-protein family includes structurally related murine (for example, p202a, p202b, p204, and Aim2) and human (for example, AIM2 and IFI16) proteins. All proteins in the family share a partially conserved repeat of 200-amino acid residues (also called HIN-200 domain) in the C-terminus. Additionally, most proteins (except the p202a and p202b proteins) also share a protein-protein interaction pyrin domain (PYD) in the N-terminus. The HIN-200 domain contains two consecutive oligosaccharide/oligonucleotide binding folds (OB-folds) to bind double stranded DNA (dsDNA). The PYD domain in proteins allows interactions with the family members and an adaptor protein ASC. Upon sensing cytosolic dsDNA, Aim2, p204, and AIM2 proteins recruit ASC protein to form an inflammasome, resulting in increased production of proinflammatory cytokines. However, IFI16 protein can sense cytosolic as well as nuclear dsDNA. Interestingly, the IFI16 protein contains a nuclear localization signal (NLS). Accordingly, the initial studies had indicated that the endogenous IFI16 protein is detected in the nucleus and within the nucleus in the nucleolus. However, several recent reports suggest that subcellular localization of IFI16 protein in nuclear versus cytoplasmic (or both) compartment depends on cell type. Given that the IFI16 protein can sense cytosolic as well as nuclear dsDNA and can initiate different innate immune responses (production of IFN-β versus proinflammatory cytokines), here we evaluate the experimental evidence for the regulation of subcellular localization of IFI16 protein in various cell types. We conclude that further studies are needed to understand the molecular mechanisms that regulate the subcellular localization of IFI16 protein.
authors.affiliation: Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, P. O. Box-670056, Cincinnati, OH 45267, USA.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Veeranki
authors.forename: Divaker
authors.initials: D
authors.lastname: Choubey
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007372:Interferons / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000276:immunology* / Q000378:metabolism*; D010750:Phosphoproteins / Q000276:immunology* / Q000378:metabolism*
chemical_list: C489664:Ifi16 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; C076700:IFI16 protein, human; D004247:DNA; D007372:Interferons