Interferon-inducible p200-family protein IFI16, an innate immune sensor for cytosolic and nuclear double-stranded DNA: Regulation of subcellular localization

doi:10.1016/j.molimm.2011.11.004

Molecular Immunology

Volume 49, Issue 4, January 2012, Pages 567-571

https://doi.org/10.1016/j.molimm.2011.11.004 Get rights and content

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.

Highlights

► The p200-family protein IFI16 is a newly identified DNA sensor. ► The IFI16 protein can sense cytosolic as well as nuclear DNA to initiate different innate immune responses. ► Increased levels of the IFI16 protein are associated with lupus susceptibility. ► Subcellular localization of IFI16 protein is cell type-dependent. ► Several factors may regulate subcellular localization of IFI16 protein.

Section snippets

The p200-family protein IFI16

Interferon (IFN)-inducible p200 family proteins in humans include IFI16, MNDA, IFIX, and AIM2 (encoded by the IFI16, MNDA, IFIX, and AIM2 genes) (Asefa et al., 2004, Choubey et al., 2008, Johnstone and Trapani, 1999, Ludlow et al., 2005, Mondini et al., 2010, Ouchi and Ouchi, 2008). These proteins share a partially conserved repeat of 200-amino acid residues (the HIN-200 domain) towards the C-terminus, which allows these proteins to bind dsDNA (Dawson and Trapani, 1995b, Yan et al., 2008). Most

Subcellular localization of IFI16 protein

As noted above, the amino terminus of IFI16 protein contains a bi-partite nuclear localization signal (NLS; Briggs et al., 2001). Accordingly, a study noted that nuclear localization signal in IFI16 protein is sufficient to drive the nuclear localization of the β-Gal fusion protein (Briggs et al., 2001). However, the study noted the following deviations from the conventional nuclear import mechanisms: (i) the lack of strong binding of IFI16 NLS-fusion proteins with the importin heterodimers;

Conclusions and future directions

It is likely that the subcellular localization of the endogenous IFI16 protein depends on the cell type and several factors described above. Given that the IFI16 protein can modulate diverse cellular functions, including inhibition of cell growth, modulation of apoptosis, inflammatory responses, DNA surveillance, and cellular senescence, it is of significance to correlate these various functions of IFI16 protein with its subcellular localization (cytoplasmic versus nuclear or both). It is

Disclosures

No competing financial interests exist.

Acknowledgments

The work in the laboratory has been supported by grant awards from the National Institutes of Health (AI066261 and AG025036) and Merit Awards from the Department of Veterans Affairs to D.C.

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¹: Current address: Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.

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Published by Elsevier Ltd.

ReviewInterferon-inducible p200-family protein IFI16, an innate immune sensor for cytosolic and nuclear double-stranded DNA: Regulation of subcellular localization

Abstract

Highlights

Section snippets

The p200-family protein IFI16

Subcellular localization of IFI16 protein

Conclusions and future directions

Disclosures

Acknowledgments

Biochem. Biophys. Res. Commun.

FEBS Lett.

Blood Cells. Mol. Dis.

Mol. Cell. Proteomics

Biochem. Biophys. Res. Commun.

Int. J. Biochem. Cell Biol.

Cell Host Microbe

Structure

Exp. Cell Res.

Mol. Cell

J. Biol. Chem.

Biochim. Biophys. Acta

A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway

Oncogene

Interferon-inducible factor 16 is a novel modulator of glucocorticoid action

FASEB J.

Novel properties of the protein kinase CK2-site-regulated nuclear-localization sequence of the interferon-induced nuclear factor IFI 16

Biochem. J

Activation of inflammasomes require intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain

J. Immunol.

An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome

Nat. Immunol.

Interferon-inducible IFI16 protein in human cancers and autoimmune diseases

Front. Biosci.

Interferon-inducible p200-family proteins as novel sensors of cytoplasmic DNA: role in inflammation and autoimmunity

J. Interferon Cytokine Res.

Interferon action: cytoplasmic and nuclear localization of the interferon-inducible 52-kD protein that is encoded by the Ifi200 gene from the gene 200-cluster

J. Interferon Res.

Review
Interferon-inducible p200-family protein IFI16, an innate immune sensor for cytosolic and nuclear double-stranded DNA: Regulation of subcellular localization