The Complicated Evolutionary Diversification of the Mpeg-1/Perforin-2 Family in Cnidarians

Abstract

The invertebrate innate immune system is surprisingly complex, yet our knowledge is limited to a few select model systems. One understudied group is the phylum Cnidaria (corals, sea anemones, etc.). Cnidarians are the sister group to Bilateria and by studying their innate immunity repertoire, a better understanding of the ancestral state can be gained. Corals in particular have evolved a highly diverse innate immune system that can uncover evolutionarily basal functions of conserved genes and proteins. One rudimentary function of the innate immune system is defense against harmful bacteria using pore forming proteins. Macrophage expressed gene 1/Perforin-2 protein (Mpeg-1/P2) is a particularly important pore forming molecule as demonstrated by previous studies in humans and mice, and limited studies in non-bilaterians. However, in cnidarians, little is known about Mpeg-1/P2. In this perspective article, we will summarize the current state of knowledge of Mpeg-1/P2 in invertebrates, analyze identified Mpeg-1/P2 homologs in cnidarians, and demonstrate the evolutionary diversity of this gene family using phylogenetic analysis. We will also show that Mpeg-1 is upregulated in one species of stony coral in response to lipopolysaccharides and downregulated in another species of stony coral in response to white band disease. This data presents evidence that Mpeg-1/P2 is conserved in cnidarians and we hypothesize that it plays an important role in cnidarian innate immunity. We propose that future research focus on the function of Mpeg-1/P2 family in cnidarians to identify its primary role in innate immunity and beyond.

Breaching the Bacterial Envelope: The Pivotal Role of Perforin-2 (MPEG1) Within Phagocytes

“…Nevertheless in recent years vertebrate studies have established that Perforin-2 has broad spectrum bactericidal activity that significantly limits pathogen proliferation and dissemination in vivo ( 15 , 19 , 26 , 52 – 54 , 57 , 72 , 90 ). There is also evidence to suggest that Perforin-2 functions similarly in invertebrates; although, such studies are hampered by the lack of animal and tractable cell culture models ( 27 , 28 , 30 , 31 , 33 , 38 , 39 ). The recent structural determinations of both mouse and human Perforin-2 polymers have further provided significant insight with regards to the mechanism(s) of pore formation ( 20 , 21 ).…”

“…This differential effect is suggestive of a pathogenic countermeasure deployed to defeat Perforin-2. Reduced Mpeg1 expression has also been documented in the corals Acropora cerviconis and Acropora palmata when they present with white band disease ( 28 , 39 ). Although the etiological agent of white band disease is currently unknown, it has been suggested to be bacterial ( 40 ).…”

“…Mpeg1 expression is upregulated in the sponge Suberites domuncula following LPS challenge relative to untreated animals ( 27 ). Similarly, LPS has been shown to induce the expression of Mpeg1 in the stony coral Pocillopora damicornis ( 28 ). Mpeg1 mRNA was significantly upregulated in the brain, head kidney, heart, liver, intestine, and spleen of the starry flounder Platichthys stellatus following infection with Streptococcus parauberis ( 29 ).…”

From Species to Regional and Local Specialization of Intestinal Macrophages

“…The ability to phagocyte and move in the mesoglea makes the amoebocytes very similar to mesodermal MFs. Additionally, the presence in these animals of conserved innate defense mechanisms, such as PRRs and pore-forming proteins (e.g., the MF-expressed gene 1 protein, Mpeg1), supports the participation of these amoebocytes in innate immunity (Brennan and Gilmore, 2018 ; Walters et al, 2020 ).…”

Ancient but Not Forgotten: New Insights Into MPEG1, a Macrophage Perforin-Like Immune Effector

“…MPEG1 is postulated to represent the closest paralog of the common MACPF ancestor gene in metazoa (65,66). Bioinformatic analyses reveal that complete MPEG1 homologs can be found throughout the kingdom Animalia with exemplars identifiable in phyla including sea sponges (Porifera), sea anemones (Cnidaria) (67), comb jellies (Ctenophora) (68), flatworms (Platyhelminthes) (69), molluscs (Mollusca) (70)(71)(72)(73)(74)(75)(76) and all chordate organisms (66,77). These studies also suggest that gene duplications of MPEG1 likely gave rise to the mammalian immune effectors PRF and the terminal components of the complement system (MAC), which are observed after notochord evolution.…”