IFI16

Official Full Name

interferon gamma inducible protein 16

Organism

Homo sapiens

GeneID

3428

Background

This gene encodes a member of the HIN-200 (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats) family of cytokines. The encoded protein contains domains involved in DNA binding, transcriptional regulation, and protein-protein interactions. The protein localizes to the nucleoplasm and nucleoli, and interacts with p53 and retinoblastoma-1. It modulates p53 function, and inhibits cell growth in the Ras/Raf signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2011]

Synonyms

PYHIN2; IFNGIP1;

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Detailed Information

Among the IFN-inducible PYHIN-200 gene family, Interferon-inducible protein 16 (IFI16) exerts its multiple functions via binding to various target proteins. Thus, it has been found that IFI16 is implicated with a panel of biological activities such as antiviral immunity, inflammation, cell death and cell cycle control.

IFI16 biological functions

IFI16 Figure 1. Biological functions of IFI16.

IFI16 has been demonstrated to be a DNA sensor, which stimulates type I IFN expression upon sensing of intracellular DNA. In addition to DNA sensor, IFI16 also has wide functions range gene transcriptional regulation, chromatin remodeling, from antiviral restriction and extracellular signaling regulation (Figure 1). It has been shown that IFI16 exerts its pleiotropic functions through two major domains, one is PYRIN domain involved in homotypic protein–protein interactions and another is HIN domains mediating DNA binding. Studies have reported that the binding of IFI16 to synthetic DNA is essential for DNA-stimulated nuclear translocation of interferon regulatory factor 3 (IRF3) and NF-kB and expression of IFNβ. Besides, the interaction of IFI16 with STING directly, leading to recruitment of TANK-binding kinase 1 (TBK1), is also been demonstrated. Moreover, all these molecules above are found to play important roles in induction of IFN responses during infection with a variety of pathogens, as well as in DNA damage response. However, the detail functions of IFI16 serves as a DNA sensor still remain more investigation.

Moreover, a series of studies have demonstrated that IFI16 also acts on inflammasome activation during virus infection such as herpes simplex virus 1(HSV-1), kaposi's sarcoma-associated herpes virus (KSHV), Epstein–Barr virus (EB). Besides, accumulation studies have described IFI16 as a transcriptional regulator due to the fact that overexpression of IFI16 leads to substantial inflammatory genes expression and some specific genes inhibition. Thus, IFI16 is a gene regulator in both positive and negative regulation. It has been proposed that IFI16 exerts its function on gene regulation via the specified proteins in the promoter regions since the interaction of IFI16 and DNA is not dependent on specific sequence.

IFI16 and antiviral response

IFI16 Figure 2. Critical steps for IFI16-mediated control of Herpesvirus infections. (Dell'Oste V, et al. 2015)

Recently, it has been widely accepted that IFI16 serves as a restriction factor against virus infection. However, most viruses have evolved mechanisms to antagonize IFI16, contributing to their immune evasion. Herpesvirus family is illustrated for example (Figure 2). It has been shown that IFI16 recognizes the HSV-1 genome in the nucleus, then forms a functional inflammasome complex in cytoplasm with the apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1 (proCasp-1), cleaving and activating caspase-1 (Casp-1) and IL-1β. The migration of IFI16 has been reported to stimulate the nuclear-to-cytoplasmic signaling cascade, activating IRF-3 to promote the expression of IFN type I. Nevertheless, several reports have found the fact HSV-1 utilizes its immediate-early protein ICP0 to target IFI16 for degradation, preventing the cell from inducing IFN expression and silencing the viral genome. Additionally, IFI16 also detects HCMV-DNA and exerts its antiviral function via repressing virus replication by blocking the activity of SP1 like transcription factors on the UL54 promoter of the virus, as well as activating STING-mediated antiviral cytokine expression. It has been found that human cytomegalovirus (HCMV) antagonizes IFI16 via two major aspects. On the one hand, viral protein pUL83 directly binds to IFI16, preventing IFI16 oligomerization by on DNA. On the other hand, viral kinase pUL97 binds to IFI16 and localizes IFI16 to cytoplasm, leading to IFI16 phosphorylation in vitro. Moreover, the antiviral strategies of IFI16 on KHSV and EBV are forming a functional inflammasome which is similar to HSV-1.

References:

Dell'Oste V, et al. The interferon-inducible DNa-sensor protein IFI16: a key player in the antiviral response. New Microbiologica, 2015, 38(1):5-20.
Choubey D, et al. IFI16, an amplifier of DNA-damage response: Role in cellular senescence and aging-associated inflammatory diseases. Ageing Research Reviews, 2016, 28:27-36.
Lo C I, et al. The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters. Journal of Virology, 2015, 89(15):7506-20.
Diner B A, et al. Interactions of the Antiviral Factor Interferon Gamma-Inducible Protein 16 (IFI16) Mediate Immune Signaling and Herpes Simplex Virus-1 Immunosuppression. Molecular & Cellular Proteomics, 2015, 14(9):2341.
Jakobsen M R, et al. IFI16: At the interphase between innate DNA sensing and genome regulation. Cytokine Growth Factor Rev, 2014, 25(6):649-655.
Bawadekar M, et al. Mislocalization of the interferon inducible protein IFI16 by environmental insults: implications in autoimmunity. Cytokine & Growth Factor Reviews, 2015, 26(2):213-21.

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