ReviewThe HIN-200 family: More than interferon-inducible genes?
Introduction
The first murine HIN-200 gene, Ifi 202a, was identified in 1982, and since then, a family of five murine and four human interferon-inducible family members has been cloned and characterized. Murine HIN-200 proteins include p202a (previously referred to as p202), p202b, p203, p204, and p205 (originally named D3) while the human HIN-200 family members comprise IFI 16 (Interferon-Inducible protein 16), MNDA (Myeloid Nuclear Differentiation Antigen), AIM2 (Absent In Melanoma 2), and IFIX (IFN-inducible protein X). These proteins were initially grouped as a family because they contain conserved structural domains and motifs and are induced by IFN. Later, the HIN-200 nomenclature was adopted describing their hemopoietic expression, IFN-induction, nuclear localization, and characteristic 200 amino-acid domains. In this review, we propose that the 200 amino-acid domains be referred to as “200 X domains” where X represents the subclass of this domain and can be either A, B, or the C subclass newly identified in this review (refer to the Reclassification of the 200 X domains section for more information). Recent research in the field has revealed that the HIN-200 classification though accurate in some respects, is not appropriate for all the family members. HIN-200 proteins have a wider cellular distribution than originally thought, can be regulated by a range of exogenous stimuli other than IFN, and are not exclusively found in the nucleus. The molecular, biochemical, and biological characteristics of each family member have been assessed to varying extents and point to a role in the regulation of cell proliferation and differentiation. However, established methods for defining the physiological functions of genes such as transgenic and knock-out mouse models have not yet been successfully employed for this gene family. While all HIN-200 proteins are induced by type I and type II IFN, their role in IFN biology has not been established, and more recently, interest in the HIN-200 proteins has centered on their proposed role in autoimmunity and cancer. No true structural and functional mouse homologues of human HIN-200 proteins have been identified, but it remains possible that such homologues and other HIN-200 genes exist and await discovery. In this review, we have analyzed the location of known genes within the human and mouse HIN-200 loci and identified novel computer predicted mouse and rat HIN-200 genes. In addition, we provide an update on the functional properties of HIN-200 proteins.
Section snippets
Previously identified HIN-200 genes
The murine HIN-200 genes represent one of the earliest identified families of IFN-responsive genes following the discovery of the MHC cluster in 1986 [1]. Of the five known murine HIN-200 genes, Ifi 202a [2], Ifi 203 [3], and Ifi 204 [4] were cloned in screens for IFN-responsive genes and Ifi 205 was identified in a screen for lipopolysaccharide (LPS)-responsive genes [5]. The Ifi 202b gene is almost identical to Ifi 202a, suggesting that they may have arisen by gene duplications. Ifi 202b and
Protein structure of known and novel proteins
As shown in Fig. 4, the known HIN-200 proteins have a conserved domain structure. With the exception of p202a and p202b, they all contain a PAAD/DAPIN/Pyrin domain at their N-termini and, with the exception of the IFIXγ isoform, this is followed by either one or two copies of a C-terminal 200 X domain. The intervening ‘spacer’ regions that separate these domains in certain HIN-200 proteins are not conserved in overall sequence and size, but are rich in S/T/P residues indicating a common
Subcellular localization
HIN-200 proteins are normally localized to the nucleus. In some cases, nuclear import is mediated by a recognized nuclear localization signal (NLS), for example, p203, p204, p205, and IFIX contain basic amino-acid residues at their N-terminus and IFI 16 has a bipartite NLS [37]. The molecular events underpinning nuclear localization of p202a, AIM2, and MNDA are less clear as no recognized NLS is present in these proteins. For selected family members, localization can be assigned to specific
Function of HIN-200 proteins
Two attempts have been made to genetically manipulate HIN-200 genes in the mouse. Firstly, production of transgenic animals over-expressing p204 was attempted by expression of the Ifi 204 cDNA under control of the SV40 promoter in C57Bl/6 mice. No viable animals were produced because cell development was blocked at the four-cell stage [57]. Secondly, knock-out of Ifi 202a by homologous recombination was achieved; however, the highly homologous Ifi 202b gene was up-regulated to compensate for
Conclusions and perspectives
In this study, we have used genomic database resources to map the human, mouse, and rat HIN-200 loci and have reviewed recent developments in the field of HIN-200 biology. Using this approach, we have comprehensively mapped the existing characterized HIN-200 genes and have predicted three novel rat and four novel mouse HIN-200 genes. The reason for the existence of such a large number of HIN-200 genes is not known. Interestingly, we have identified direct homologues of AIM2 in the mouse and rat
Acknowledgments
The authors would like to acknowledge Scott Fraser, Rachael Roberts, Steven Williams, Sheena Wong, and Sharon Wright for their input into the sequence analysis of the human, mouse, and rat HIN-200 genes. R.W.J. is a Welcome Trust Senior fellow. L.L. is supported by an Australian Postgraduate Award from The University of Melbourne, Australia. This work was funded by a program grant from the NHMRC of Australia.
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