Abstract
BackgroundProteins of the mammalian PYHIN (IFI200/HIN-200) family are involved in defence against infection through recognition of foreign DNA. The family member absent in melanoma 2 (AIM2) binds cytosolic DNA via its HIN domain and initiates inflammasome formation via its pyrin domain. AIM2 lies within a cluster of related genes, many of which are uncharacterised in mouse. To better understand the evolution, orthology and function of these genes, we have documented the range of PYHIN genes present in representative mammalian species, and undertaken phylogenetic and expression analyses.ResultsNo PYHIN genes are evident in non-mammals or monotremes, with a single member found in each of three marsupial genomes. Placental mammals show variable family expansions, from one gene in cow to four in human and 14 in mouse. A single HIN domain appears to have evolved in the common ancestor of marsupials and placental mammals, and duplicated to give rise to three distinct forms (HIN-A, -B and -C) in the placental mammal ancestor. Phylogenetic analyses showed that AIM2 HIN-C and pyrin domains clearly diverge from the rest of the family, and it is the only PYHIN protein with orthology across many species. Interestingly, although AIM2 is important in defence against some bacteria and viruses in mice, AIM2 is a pseudogene in cow, sheep, llama, dolphin, dog and elephant. The other 13 mouse genes have arisen by duplication and rearrangement within the lineage, which has allowed some diversification in expression patterns.ConclusionsThe role of AIM2 in forming the inflammasome is relatively well understood, but molecular interactions of other PYHIN proteins involved in defence against foreign DNA remain to be defined. The non-AIM2 PYHIN protein sequences are very distinct from AIM2, suggesting they vary in effector mechanism in response to foreign DNA, and may bind different DNA structures. The PYHIN family has highly varied gene composition between mammalian species due to lineage-specific duplication and loss, which probably indicates different adaptations for fighting infectious disease. Non-genomic DNA can indicate infection, or a mutagenic threat. We hypothesise that defence of the genome against endogenous retroelements has been an additional evolutionary driver for PYHIN proteins.
Highlights
Proteins of the mammalian Pyrin and HIN domain-containing (PYHIN) (IFI200/HIN-200) family are involved in defence against infection through recognition of foreign DNA
The PYHIN Gene Locus in Mouse The PYHIN gene cluster is found in a syntenic region in many mammals, located between the Cell Adhesion Molecule 3 (CADM3) gene and a collection of olfactory receptors and spectrin alpha chain (SPTA1), on chromosome 1q band H3 in mouse, 1q23 in human, and 13q24 in rat (Figure 1)
The evolution of the first PYHIN protein is likely to have provided a new effector system for combating the threats indicated by stray DNA within mammalian cells
Summary
Proteins of the mammalian PYHIN (IFI200/HIN-200) family are involved in defence against infection through recognition of foreign DNA. AIM2 was necessary for effective control of Francisella tularensis and MCMV infection of mice [6,7,11] Another PYHIN family member, human IFI16, was shown to mediate inflammasome responses to Kaposi’s sarcoma virus DNA in the nucleus [12]. IFI16 is not the only contender for such a role in DNA recognition, as recent work suggests that the unrelated helicase protein DDX41 is the DNAbinding protein primarily required for the early induction of signalling leading to IFN-β production whilst IFI16-mediated responses to DNA may prolong the induction of IFN-β later in the response [19] Both IFI16 and DDX41 were reported to bind to STING [13,19]. Study of the PYHIN gene family has been hampered by the complexity of the family in mouse, and a lack of understanding of orthology between mouse and human genes
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