P200 family protein IFI204 negatively regulates type I interferon responses by targeting IRF7 in nucleus

Abstract

Interferon-inducible p200 family protein IFI204 was reported to be involved in DNA sensing, and subsequently induces the production of type I interferons and proinflammatory mediators. However, its function in the regulation of antiviral innate immune signaling pathway remains unclear. Here we reported a novel role of IFI204 that specifically inhibits the IRF7-mediated type I interferons response during viral infection. IFI204 and other p200 family proteins are highly expressed in mouse hepatitis coronavirus-infected bone marrow-derived dendritic cells. The abundant IFI204 could significantly interact with IRF7 in nucleus by its HIN domain and prevent the binding of IRF7 with its corresponding promoter. Moreover, other p200 family proteins that possess HIN domain could also inhibit the IRF7-mediated type I interferons. These results reveal that, besides the positive regulation function in type I interferon response at the early stage of DNA virus infection, the interferon-inducible p200 family proteins such as IFI204 could also negatively regulate the IRF7-mediated type I interferon response after RNA virus infection to avoid unnecessary host damage from hyper-inflammatory responses.

The Functional and Antiviral Activity of Interferon Alpha-Inducible IFI6 Against Hepatitis B Virus Replication and Gene Expression

“…TNF-α and IFN-γ induced IL-32 in primary human hepatocytes and hepatoma cells that regulate the transcription of HBV core promoter by downregulating HNF1-α and HNF4-α. Similarly, IFN-γ-mediated anti-HBV activity is contributed by hepatocystin that downregulates viral enhancer activity by overexpression of HNF4-α ( 31 – 34 , 47 , 48 ). According to this context, our results indicate that IFI6 inhibit HBV replication by interacting with EnhII/Cp region without dysregulation of various liver enriched transcription factors, including HNF1α, HNF4α, PGC-1α, and C/EBPα ( Figure 4C ) ( 34 ).…”

“…ChIP assay was carried out as described previously ( 31 ) with a ChIP Assay kit (Beyotime, catalog number P2078) according to the manufacturer’s instructions. Briefly, HepG2 cells were seeded into a 10 cm cell culture dish and transfected with pHBV1.3 (5 µg) with IFI6 (5 µg) or control vector (pCAGGS, 5 µg).…”

“…The GST-IFI6 protein was mixed in a binding buffer containing 400 mM Tris-HCl [pH 8.0], 50 mM DTT) and incubated for 30 minutes on ice as previously described ( 31 ). The CY5-labeled probe of the HBV EnhII 1715-1770 nt and non-competitive sequence (probe sequence is shown in Supplementary Table 2 ) was added to the protein mix and incubated for 30 minutes at room temperature.…”

Coronavirus infections and immune responses

“…As the host's major antiviral molecules, IFNs limit virus spread, and play an immunomodulatory role to promote macrophage phagocytosis of antigens, as well as NK cells restriction of infected target cells and T/B cells. Thus, blocking the production of IFNs has a direct effect on the survival of the virus in the host 39,40 . So far, PRRs are divided into three types according to their forms of existence 41 : the membrane type includes TLR2, TLR4, mannose receptor (MR), scavenger receptor (SR); the secretory type comprises mannose‐binding lectin (MBL) and C‐reactive protein (CRP); the cytoplasmic type consists of TLR3, TLR7/8, and NLRs.…”

SARS‐CoV‐2: A comprehensive review from pathogenicity of the virus to clinical consequences

“…Humans are capable of expressing one IFN‐beta, 13 subtypes of IFN‐alphas, and one each of IFN‐kappa and IFN‐omega. The type I interferon responses which is composed of alpha/beta‐IFNs 62 and its downstream cascade which culminate in immunomodulation, controlling viral replication, and induction of effective adaptive immune response (NK cells, macrophage, and T/B lymphocytes) is not functional against COVID‐19 as the SARS‐CoV‐2 has inhibited the induction, production, 63,64 and the JAK‐STAT signaling pathway of the interferon 61 …”