What is it about?
The host immune system is essential to combat infection. Key front-line immune defences against infection are these host-encoded antibiotics called "antimicrobial peptides" Antimicrobial peptide genes often encode multiple mature products, interspersed by furin cleavage sites. Antimicrobial peptide genes have also been implicated in non-immune functions in neurology, including ways they affect behaviour or neurodegenerative diseases. How these genes accomplish these contrasting roles is unclear: do the same products combat pathogens and also mediate behaviours? We studied a recently-characterized immune family that encodes both antifungal peptides and another uncharacterized peptide product. Using an evolutionary approach, we realized that the two kinds of products (antifungals and this uncharacterized peptide) are actually used in different tissues and different contexts. By looking at gene duplications, we saw that the uncharacterized peptide was a key component of genes involved in the nervous system, while the antifungal peptides were key components involved in genes that respond to infection. Our study clarifies that the way antimicrobial peptide genes can be involved in different tissues and contexts isn't necessarily because the same peptides are functioning in dual roles. Instead, paying close attention to how the gene is processed, and whether the gene encodes multiple products, some antimicrobial peptide genes may do these two very different jobs using two very different products.
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Why is it important?
There is a tendency for research to focus on genes at the gene level, or at the level of the antimicrobial peptides they are known for. Our study draws attention to how antimicrobial peptide genes are not simple one-product genes. A lot of research manipulates model cell lines or systems by supplementing with the commonly-used antimicrobial peptides in a petri dish. But for understanding how these genes affect neurological processes in live animals, we need to step back and consider the way the gene/protein is processed, and whether any uncharacterized products could explain their roles in neurology totally independent from their famous antimicrobial products.
Perspectives
One human immune gene that is very well-studied is the antimicrobial peptide "Cathelicidin" or "LL37." What's not so well-known is that the famous Cathelicidin peptide is just one of two gene products. The second gene product, called the Cathelin domain, is poorly-understood: even though the gene family is united by this peptide, it's function is totally unknown! That's a situation very similar to the peptide studied here (Baramicin). The famous immune peptides are found at the tail of the precursor protein, just like Cathelicidin. But the peptide coded at the head of the precursor protein is uncharacterized in both Cathelicidin and Baramicin. Our study suggests that this uncharacterized protein is not strictly an immune protein, and instead might play some role in the nervous system. Is the same true of Cathelicidin? Studying Cathelin more might help us learn how the Cathelicidin gene impacts the nervous system in a way that's independent of LL37. Note: the gene name "Baramicin" was inspired by Eiichiro Oda's character "Buggy" from the manga One Piece, whose body can split into multiple functional products!
Mark Hanson
University of Exeter
Read the Original
This page is a summary of: Repeated truncation of a modular antimicrobial peptide gene for neural context, PLoS Genetics, June 2022, PLOS,
DOI: 10.1371/journal.pgen.1010259.
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