The mammalian PYHIN gene family: Phylogeny, evolution and expression

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.

The emerging role of human PYHIN proteins in innate immunity: Implications for health and disease

“…Given the complexity of the PYHIN family in mouse, which have at least 13 members [7,73] it may be difficult to determine the correlation if any, with data from humans studies. Although human IFI16 and mouse p204 have been shown to function similarly, and have a similar domain structure containing a PYRIN domain and two HIN domains, human and mouse AIM2 are the only direct orthologues identified between these species based on the phylogenetic analyses of both HIN and pyrin domains [7,73]. While human and mouse PYHINs such as IFI16 and p204 appear to be functional orthologues, it will nonetheless be important to bear in mind the many differences between these two systems.…”

Inflammasomes and its importance in viral infections

“…ALRs are localised in the cytoplasm and nucleus; they consist of a PYD domain and a certain number of HIN200 domains, which bind dsDNA inactive IL-1b and IL-18 into their active forms [17]. The inflammasome plays an important role in the innate immune pathway and regulates at least two protective responses of the host: the secretion of proinflammatory cytokines (IL-1b and IL-18) and the induction of pyroptosis, which is a form of cell death [18,19]. Although several studies have identified diverse inflammasomes with activities against a broad range of pathogens, certain inflammasomes, such as the NLRP3, AIM2, and RIG-I inflammasomes, have been found to be highly specific and important in mediating the host response to viral infection [11,20].…”

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

“…p202 has been suggested to be a mouse lupus susceptibility factor (43,63), although this remains to be proved. The gene encoding p202, Ifi202, has variable copy number in different strains (3), all located within the Nba2 lupussusceptibility locus at 1q22, and p202 is highly expressed in NZB and other lupus-prone mouse strains (43, 63, 64). The Nba2 congenic strain has this region of chromosome 1 from NZB backcrossed onto C57BL/6.…”

“…mRNA and microRNA quantitative RT-PCR analysis RNA preparation, cDNA synthesis, and quantitative RT-PCR were conducted as outlined previously (3). Primers targeting murine genes included Nlrp3-forward 59-GCT CCA ACC ATT CTC TGA CC-39, Nlrp3-reverse 59-AAG TAA GGC CGG AAT TCA CC-39, Hprt-forward 59-CAG TCC CAG CGT CGT GAT TAG-39 and Hprt-reverse 59-AAA CAC TTT TTC CAA ATC CTC GG-39.…”

“…Inflammasome complex formation depends on the oligomerization of an initiator protein, either a member of the Nod-like receptor family (such as NLR family, pyrin domain containing 3 [NLRP3] or NLR family, CARD domain containing 4 [NLRC4]) or absent in melanoma 2 (AIM2), which is a member of the pyrin and HIN domain containing (PYHIN) protein family (3). These clustered proteins recruit the adapter molecule apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and then procaspases.…”