A family of unusual immunoglobulin superfamily genes in an invertebrate histocompatibility complex

Abstract

Most colonial marine invertebrates are capable of allorecognition, the ability to distinguish between themselves and conspecifics. One long-standing question is whether invertebrate allorecognition genes are homologous to vertebrate histocompatibility genes. In the cnidarian Hydractinia symbiolongicarpus, allorecognition is controlled by at least two genes, Allorecognition 1 ( Alr1 ) and Allorecognition 2 ( Alr2 ), which encode highly polymorphic cell-surface proteins that serve as markers of self. Here, we show that Alr1 and Alr2 are part of a family of 41 Alr genes, all of which reside in a single genomic interval called the Allorecognition Complex (ARC). Using sensitive homology searches and highly accurate structural predictions, we demonstrate that the Alr proteins are members of the immunoglobulin superfamily (IgSF) with V-set and I-set Ig domains unlike any previously identified in animals. Specifically, their primary amino acid sequences lack many of the motifs considered diagnostic for V-set and I-set domains, yet they adopt secondary and tertiary structures nearly identical to canonical Ig domains. Thus, the V-set domain, which played a central role in the evolution of vertebrate adaptive immunity, was present in the last common ancestor of cnidarians and bilaterians. Unexpectedly, several Alr proteins also have immunoreceptor tyrosine-based activation motifs and immunoreceptor tyrosine-based inhibitory motifs in their cytoplasmic tails, suggesting they could participate in pathways homologous to those that regulate immunity in humans and flies. This work expands our definition of the IgSF with the addition of a family of unusual members, several of which play a role in invertebrate histocompatibility.

Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity

“…Our study joins a growing body of work demonstrating the transformative power of structural modeling in identifying evolutionary connections 10 , 54 , 55 and informing mechanistic study. 11 The ability to detect distant homology is especially important for hybrid proteins such as C1, where global homology searches may be inconclusive ( Figures 3A – 3C ). Tools such as Foldseek 56 and the AlphaFold-based domain identification tool DPAM 57 are beginning to address these limitations and will empower future studies of structural homology, with continuing computational advances unlocking new biology.…”

“…Recent advances in structural modeling such as those implemented in AlphaFold2 8 have the potential to bridge this gap, and the utility of this breakthrough in identifying cryptic homology is already being appreciated. For example, ab initio modeling has been used to broadly identify pathogen mimics of host proteins, 9 to identify evolutionary connections among pathogen effectors, 10 to expand an understanding of immunoglobulin gene family evolution, 11 and to provide insight into the distant cellular origins of structural proteins found in viruses. 12 In this study, we use AlphaFold to enable searches for hidden homology in viral proteomes and inform the mechanistic study of host-pathogen interfaces.…”

Structural homology screens reveal poxvirus-encoded proteins impacting inflammasome-mediated defenses

“…Freed from constraints in host genomes, individual domains and combinations thereof may diverge to acquire new functions, with viral genomes serving as a "testbed" of evolutionary innovation. Our study joins a growing body of work demonstrating the transformative power of structural modeling in identifying evolutionary connections 11,50,51 and informing mechanistic study 12 . The ability to detect distant homology is especially important for "hybrid" proteins such as C1, where global homology searches may be inconclusive (Figures 3A-C).…”

“…Recent advances in structural modeling such as implemented in AlphaFold2 9 have the potential to bridge this gap, and the utility of this breakthrough in identifying cryptic homology is already being appreciated. For example, ab initio modeling has been used to broadly identify pathogen mimics of host proteins 10 , to identify evolutionary connections among pathogen effectors 11 , to expand an understanding of immunoglobulin gene family evolution 12 , and to provide insight into the distant cellular origins of structural proteins found in viruses 13 . In this study, we use AlphaFold to enable searches for hidden homology in viral proteomes and test its ability to inform the mechanistic study of host-pathogen interfaces.…”

Establishment of the immunological self in juvenile Patiria pectinifera post-metamorphosis

“…The difference in allogeneic levels between these chimeras was based on the number of shared parental haplotypes; sibling chimeras from the same parents included four haplotypes, half-sibling chimeras with one shared parent included six haplotypes, and allogeneic chimeras from two sets of parents included eight haplotypes. If we assume that chimeras are tolerated if at least one of the haplotypes of the histocompatibility genes (assuming a gene complex) is compatible in P. pectinifera , as predicted from the homologous recognition responses of colonial animals such as sponges and ascidians ( 41 – 45 ), then each cell comprising sibling, half-sibling, and allogeneic chimeras will share at least one haplotype with 75.0%, 67.5%, and 37.5% of cells in the same individual, respectively. Consequently, the probability of neighboring cells sharing a haplotype is high for sibling and half-sibling chimeras, but low for allogeneic chimeras.…”