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

Abstract

Deregulated innate immune responses that result in increased levels of type I interferons (IFNs) and stimulation of IFN-inducible genes are thought to contribute to chronic inflammation and autoimmunity. One family of IFN-inducible genes is the Ifi200 family, which includes the murine (eg, Ifi202a, Ifi202b, Ifi203, Ifi204, Mndal, and Aim2) and human (eg, IFI16, MNDA, IFIX, and AIM2) genes. Genes in the family encode structurally related proteins (the p200-family proteins), which share at least one partially conserved repeat of 200-amino acid (200-AA) residues. Consistent with the presence of 2 consecutive oligonucleotide/oligosaccharide-binding folds in the repeat, the p200-family proteins can bind to DNA. Additionally, these proteins (except the p202 proteins) also contain a pyrin (PYD) domain in the N-terminus. Increased expression of p202 proteins in certain strains of female mice is associated with lupus-like disease. Interestingly, only the Aim2 protein is conserved between the mouse and humans. Several recent studies have provided evidence that the Aim2 and p202 proteins can recognize DNA in cytoplasm and the Aim2 protein upon sensing DNA can form a caspase-1-activating inflammasome. In this review, we discuss how the ability of p200-family proteins to sense cytoplasmic DNA may contribute to the development of chronic inflammation and associated diseases.

FIG. 1.

Sequence alignment of the murine (Aim2; the NCBI accession # NP001013801) and human (AIM2; accession #AAH10940) absent in melanoma 2 proteins. The amino acid residues that are identical between the 2 proteins are indicted by asterisks (*). The amino acid residues of a protein–protein interaction motif [(I/M) (F/L) HATVA (T/S)], which is conserved in all 200-AA repeats in the p200-family proteins, and a potential pRb-binding motif (LxCxE-like motif) are shown in bold. Substitution of phenylalanine (Phe¹⁶⁵) with alanine (Ala) amino acid residue in human AIM2 protein, which resulted in diminished DNA binding (Bürckstümmer and others 2009), is also indicated in bold. This Phe residue is conserved between the murine and human absent in melanoma 2 proteins.

FIG. 2.

Schematic representation of structural and functional domains in the murine p202 and Aim2 proteins. Vertical line box in the N-terminus of the p202 protein denotes a unique region that is not conserved between p202 and Aim2 proteins. Light gray and dark gray boxes in the p202 protein denote a type-A and a type-B 200-AA repeat, respectively (Ludlow and others 2005). White box in the Aim2 protein denotes a type-C 200-AA repeat. The A-type repeat in the p202 protein shares 24.4% amino acid identity with the B repeat and 35.5% amino acid identity with the C repeat in the Aim2 protein. In contrast, the B repeat in p202 protein shares 33.3% amino acid identity with the C repeat in the Aim2 protein. Dotted box in the N-terminus of the Aim2 protein denotes the pyrin (PYD) domain. Each 200-AA repeat is predicted to contain 2 consecutive OB-folds (Albrecht and others 2005). The amino acid residues of a protein–protein interaction motif [(I/M) (F/L) HATVA (T/S)] and a potential pRb-binding motif (LxCxE-like motif) are also shown.

FIG. 3.

Schematic structural representation of the predicted isoforms of the human and murine absent in melanoma 2 proteins and their predicted overall subcellular localization. The NCBI accession numbers for the isoforms are indicated in parenthesis. Dotted box in the N-terminus of the Aim2 protein denotes the pyrin (PYD) domain. White box in the Aim2 protein denotes the type-C 200-AA repeat.

FIG. 4.

A proposed model for physical and functional interactions between the murine Aim2 and p202 proteins. The model is based on demonstrated preferential binding of the 200-AA repeat in human AIM2 protein, which shares 55.7% amino acid identity with the murine Aim2 protein, with dsDNA (synthetic, pathogen- or host-derived) and the pyrin domain-dependent recruitment of the ASC adaptor protein that resulted in the formation of AIM2 inflammasome (Schroder and others ; Krieg 2009). The AIM2 inflammasome activated caspase-1, which promoted the processing of proinflammatory cytokines, such as pro-IL-1β and pro-IL-18. The AIM2 protein can bind to p202 (Choubey and others 2000) and the p202 protein can form homodimers (Koul and others 1998). Therefore, it has been proposed (Roberts and others ; Krieg 2009) that increased levels of the p202 protein, which depend on the promoter polymorphisms in the Ifi202 gene, levels of cytokines (eg, IFNs and IL-6), and the female sex hormone estrogen (Choubey and Panchanathan 2008) in immune cells inhibit the formation of the Aim2 inflammasome.