Nuclear interferon-inducible protein 16 promotes silencing of herpesviral and transfected DNA.
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ABSTRACT:
SUBMITTER: Orzalli MH
PROVIDER: S-EPMC3839728 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
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Project description:IFI16 is a member of the interferon-inducible HIN-200 family of nuclear proteins. It has been implicated in transcriptional regulation by modulating protein-protein interactions with p53 tumor suppressor protein and other transcription factors. However, the mechanisms of interaction remain unknown. Here, we report the crystal structures of both HIN-A and HIN-B domains of IFI16 determined at 2.0 and 2.35 Å resolution, respectively. Each HIN domain comprises a pair of tightly packed OB-fold subdomains that appear to act as a single unit. We show that both HIN domains of IFI16 are capable of enhancing p53-DNA complex formation and transcriptional activation via distinctive means. HIN-A domain binds to the basic C terminus of p53, whereas the HIN-B domain binds to the core DNA-binding region of p53. Both interactions are compatible with the DNA-bound state of p53 and together contribute to the effect of full-length IFI16 on p53-DNA complex formation and transcriptional activation.
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Project description:Non-coding RNAs represent a class of important regulators in immune response. Previously, LINC02605 was identified as a candidate regulator in innate immune response by lncRNA microarray assays. In this study, we systematically analyzed the functions and the acting mechanisms of LINC02605 in antiviral innate immune response. LINC02605 was up-regulated by RNA virus, DNA virus, and type I IFNs in NF-κB and Jak-stat dependent manner. Overexpression of LINC02605 promotes RNA virus-induced type I interferon production and inhibited viral replication. Consistently, knockdown of LINC02605 resulted in reduced antiviral immune response and increased viral replication. Mechanistically, LINC02605 released the inhibition of hsa-miR-107 on the expression of phosphatase and tensin homolog (PTEN). By microRNA mimics and inhibitors, hsa-miR-107 was demonstrated to not only inhibit PTEN's expression but also negatively regulate the antiviral immune response. Knockdown of LINC02605 led to the reduction of PTEN expression both in mRNA and protein levels. Overexpression of LINC02605 had an opposite impact. Moreover, LINC02605 attenuated the serine 97 phosphorylation level of interferon regulatory factor 3 (IRF3) by promoting PTEN expression. Nucleoplasmic fragmentation assay showed that knocking down LINC02605 inhibited the nuclear translocation of IRF3, rendering the host cells more susceptible to viral invasion, while overexpression showed opposite effects. Therefore, LINC02605 is an induced lncRNA by viral infection and plays a positive feedback in antiviral immune response through modulating the nuclear translocation of IRF3.
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Project description:IFI16 (gamma-interferon-inducible protein 16), a predominantly nuclear protein involved in transcriptional regulation, also functions as an innate immune response DNA sensor and induces the IL-1? and antiviral type-1 interferon-? (IFN-?) cytokines. We have shown that IFI16, in association with BRCA1, functions as a sequence independent nuclear sensor of episomal dsDNA genomes of KSHV, EBV and HSV-1. Recognition of these herpesvirus genomes resulted in IFI16 acetylation, BRCA1-IFI16-ASC-procaspase-1 inflammasome formation, cytoplasmic translocation, and IL-1? generation. Acetylated IFI16 also interacted with cytoplasmic STING and induced IFN-?. However, the identity of IFI16 associated nuclear proteins involved in STING activation and the mechanism is not known. Mass spectrometry of proteins precipitated by anti-IFI16 antibodies from uninfected endothelial cell nuclear lysate revealed that histone H2B interacts with IFI16. Single and double proximity ligation microscopy, immunoprecipitation, EdU-genome labeled virus infection, and chromatin immunoprecipitation studies demonstrated that H2B is associated with IFI16 and BRCA1 in the nucleus in physiological conditions. De novo KSHV and HSV-1 infection as well as latent KSHV and EBV infection induces the cytoplasmic distribution of H2B-IFI16, H2B-BRCA1 and IFI16-ASC complexes. Vaccinia virus (dsDNA) cytoplasmic replication didn't induce the redistribution of nuclear H2B-IFI16 or H2B into the cytoplasm. H2B is critical in KSHV and HSV-1 genome recognition by IFI16 during de novo infection. Viral genome sensing by IFI16-H2B-BRCA1 leads to BRCA1 dependent recruitment of p300, and acetylation of H2B and IFI16. BRCA1 knockdown or inhibition of p300 abrogated the acetylation of H2B-IFI16 or H2B. Ran-GTP protein mediated the translocation of acetylated H2B and IFI16 to the cytoplasm along with BRCA1 that is independent of IFI16-ASC inflammasome. ASC knockdown didn't affect the acetylation of H2B, its cytoplasmic transportation, and the association of STING with IFI16 and H2B during KSHV infection. Absence of H2B didn't affect IFI16-ASC association and cytoplasmic distribution and thus demonstrating that IFI16-H2B complex is independent of IFI16-ASC-procaspase-1-inflammasome complex formed during infection. The H2B-IFI16-BRCA1 complex interacted with cGAS and STING in the cytoplasm leading to TBK1 and IRF3 phosphorylation, nuclear translocation of pIRF3 and IFN-? production. Silencing of H2B, cGAS and STING inhibited IFN-? induction but not IL-1? secretion, and cGAMP activity is significantly reduced by H2B and IFI16 knockdown during infection. Silencing of ASC inhibited IL-1? secretion but not IFN-? secretion during de novo KSHV and HSV-1 infection. These studies identify H2B as an innate nuclear sensor mediating a novel extra chromosomal function, and reveal that two IFI16 complexes mediate KSHV and HSV-1 genome recognition responses, with recognition by the IFI16-BRCA1-H2B complex resulting in IFN-? responses and recognition by IFI16-BRCA1 resulting in inflammasome responses.
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Project description:IFI16, member of the IFN-inducible PYHIN-200 gene family, modulates proliferation, survival and differentiation of different cell lineages. In particular, IFI16 expression, which is regulated during the differentiation of B cells, was recently studied in B-CLL as well. Here, we compared IFI16 expression in several lymphomas including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma and mantle cell lymphoma with respect to normal cell counterparts. We observed that IFI16 expression was significantly deregulated only in mantle cell lymphoma (p < 0.05). Notably, IFI16 was associated with the expression of genes involved in interferon response, cell cycle, cell death and proliferation and, interestingly, lipid and glucose metabolism, suggesting that IFI16 deregulation might be associated with relevant changes in cell biology. In our group of mantle cell lymphoma samples a correlation between patient survival and IFI16 expression was not detected even though mantle cell lymphoma prognosis is known to be associated with cell proliferation. Altogether, these results suggest a complex relationship between IFI16 expression and MCL which needs to be analyzed in further studies.
| S-EPMC6893061 | biostudies-literature
Project description:ObjectiveTo examine the association between anti-interferon-inducible protein 16 (anti-IFI-16) antibodies and clinical features of scleroderma.MethodsSera from a discovery sample of 94 patients with scleroderma and 47 healthy controls were assayed for anti-IFI-16 antibodies by enzyme-linked immunosorbent assay, and associations were examined using regression analyses. Since anti-IFI-16 autoantibodies were found to be strongly associated with digital gangrene in the discovery sample, a subsequent case-control study (with subjects matched 1:1 on disease duration) was designed for further exploration. Cases were patients with scleroderma and digital gangrene, while controls were patients with scleroderma and Raynaud's phenomenon alone (n = 39 matched pairs). Nonparametric, unadjusted matched pairs analysis as well as univariate and multivariable conditional logistic regression analyses were performed.ResultsIn the discovery sample, anti-IFI-16 antibodies were more prevalent in patients with scleroderma than in healthy controls (18% versus 2%; P = 0.01). Patients with anti-IFI-16 antibodies, compared to anti-IFI-16 antibody-negative patients, were more likely to have limited scleroderma (77% versus 46%; P = 0.03), a longer disease duration (median 15.2 years [interquartile range 10.6-18.3] versus 6.0 years [interquartile range 3.4-13.8]; P < 0.01), digital gangrene (24% versus 4%; P = 0.02), and a low diffusing capacity for carbon monoxide (DLco) (P < 0.01). In the case-control study, 35 (45%) of 78 patients were anti-IFI-16 antibody positive. Anti-IFI-16 antibody levels were significantly higher in cases with digital gangrene than in matched controls (P = 0.02). In analyses adjusted for age, cutaneous scleroderma subtype, smoking, and DLco, high anti-IFI-16 antibody levels were associated with the presence of digital gangrene (adjusted odds ratio 2.3, 95% confidence interval 1.0-5.6, P = 0.05). The odds of having digital gangrene increased with higher anti-IFI-16 antibody titers, in a dose-dependent manner.ConclusionAnti-IFI-16 antibodies are associated with digital gangrene in patients with scleroderma. Longitudinal prospective studies exploring anti-IFI-16 antibodies as a disease biomarker, and biologic studies investigating the pathogenicity of these antibodies, are warranted.
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Project description:BackgroundLupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus (SLE). However, the current management of LN remains unsatisfactory due to sneaky symptoms during early stages and lack of reliable predictors of disease progression.MethodsBioinformatics and machine learning algorithms were initially used to explore the potential biomarkers for LN development. Identified biomarker expression was evaluated by immunohistochemistry (IHC) and multiplex immunofluorescence (IF) in 104 LN patients, 12 diabetic kidney disease (DKD) patients, 12 minimal change disease (MCD) patients, 12 IgA nephropathy (IgAN) patients and 14 normal controls (NC). The association of biomarker expression with clinicopathologic indices and prognosis was analyzed. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were utilized to explore potential mechanisms.ResultsInterferon-inducible protein 16 (IFI16) was identified as a potential biomarker for LN. IFI16 was highly expressed in the kidneys of LN patients compared to those with MCD, DKD, IgAN or NC. IFI16 co-localized with certain renal and inflammatory cells. Glomerular IFI16 expression was correlated with pathological activity indices of LN, while tubulointerstitial IFI16 expression was correlated with pathological chronicity indices. Renal IFI16 expression was positively associated with systemic lupus erythematosus disease activity index (SLEDAI) and serum creatinine while negatively related to baseline eGFR and serum complement C3. Additionally, higher IFI16 expression was closely related to poorer prognosis of LN patients. GSEA and GSVA suggested that IFI16 expression was involved in adaptive immune-related processes of LN.ConclusionRenal IFI16 expression is a potential biomarker for disease activity and clinical prognosis in LN patients. Renal IFI16 levels may be used to shed light on predicting the renal response and develop precise therapy for LN.
| S-EPMC10314472 | biostudies-literature
Project description:Psoriasis is a common chronic inflammatory skin disease characterized by epidermal hyperplasia and dermal inflammation. Keratinocyte activation is known to play a critical role in psoriasis, but the underlying mechanism remains unclear. Interferon-inducible protein 16 (IFI16), an innate immune system sensor, is reported to affect keratinocyte function. We therefore hypothesized that IFI16 promotes psoriasis by modulating keratinocyte activation. In the present study, we cinfirmed that IFI16 was overexpressed in epidermal keratinocytes of psoriasis patients. In addition, psoriasis-related cytokines, including IFN-γ, TNF-α, IL-17 and IL-22, induced IFI16 up-regulation in keratinocytes via activation of STAT3 signaling. We also observed that IFI16 activated the TBK1-NF-κB signaling, leading to the production of CXCL10 and CCL20. Importantly, knocking down p204, which is reported as the mouse orthologous of human IFI16, inhibited epidermal hyperplasia in mice with imiquimod-induced psoriasiform dermatitis. These findings indicate that IFI16 plays a critical role in the pathogenesis of psoriasis and may be a potential therapeutic target.
| S-EPMC4853747 | biostudies-literature
Project description:Activation of inflammasomes has been reported in human pancreatic adenocarcinoma (PAAD); however, the expression pattern and functional role of inflammasome-related proteins in PAAD have yet to be identified. In this study, we systemically examined the expression and role of different inflammasome proteins by retrieving human expression data. Several genes were found to be differentially expressed; however, only interferon-inducible protein 16 (IFI16) expression was found to be adversely correlated with the overall survival of PAAD patients. Overexpression of IFI16 significantly promoted tumor growth, increased tumor size and weight in the experimental PAAD model of mice, and specifically increased the population of tumor-associated macrophages (TAMs) in the tumor microenvironment. Depletion of TAMs by injection of liposome clodronate attenuated the IFI16 overexpression-induced tumor growth in PAAD. In vitro treatment of conditioned medium from IFI16-overexpressing PAAD cells induced maturation, proliferation, and migration of bone marrow-derived monocytes, suggesting that IFI16 overexpression resulted in cytokine secretion that favored the TAM population. Further analysis suggested that IFI16 overexpression activated inflammasomes, thereby increasing the release of IL-1β. Neutralization of IL-1β attenuated TAM maturation, proliferation, and migration induced by the conditioned medium from IFI16-overexpressing PAAD cells. Additionally, knockdown of IFI16 could significantly potentiate gemcitabine treatment in PAAD, which may be associated with the reduced infiltration of TAMs in the tumor microenvironment. The findings of our study shed light on the role of IFI16 as a potential therapeutic target for PAAD.
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Project description: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-? 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.
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