Evolutionary origin of mysterious human immune system molecule revealed

Biological systems can behave like siblings in several ways, including borrowing something and never returning it. This appears to be what the human immune system has done with a protein that now helps bind and regulate the subunits that make up antibodies, according to a multi-institute research collaboration. They discovered that before the immune system co-opted it during evolution, the protein originally belonged to a family of genes responsible for directing cells to the right place at the right time to meet specific needs. specific functionalities.

The researchers, including Kazuhiko Kawasaki, research associate professor of anthropology at Penn State, published their findings in the Proceedings of the National Academy of Sciences. According to the team, while this work primarily informs a fundamental understanding of a feature of the immune system and associated genes, it may also help pave the way for the design of future therapies, such as personalized immune responses.

“Everything comes from somewhere, and we believe we have found the origin of the immunoglobin junction chain (J chain), an important immune molecule,” said corresponding author Martin F. Flajnik, Department of of Microbiology and Immunology at the University of Maryland, who led the study. . Flajnik also earned his undergraduate degree in biology at Penn State in 1978 before completing his graduate work at the University of Rochester.

The J chain assembles and stabilizes two types of antibodies, called immunoglobin M (IgM) and immunoglobin A (IgA). It specifically regulates the structures of IgM and IgA molecules, which have multiple subunits, and is necessary for their movement through the mucus-producing tissues lining body structures exposed to external exposure, such as the intestine, nasal cavity and lungs.

The researchers discovered that the J chain comes from CXCL chemokines, a specific family of proteins that regulate the ability of white blood cells to move throughout the body.

“Like immunoglobin itself and human adaptive immunity, the J chain arose in jawed vertebrates, but its origin has remained mysterious since its discovery more than 50 years ago,” Flajnik said. “This discovery had never been anticipated. Locomotion driven by chemokines is a vital function of the immune system, but a totally different function from that of the J chain!”

During evolution, new genes are often generated from genes that reside physically close to each other on the chromosome, and these genes usually remain grouped together even if they evolve with different but similar functions, but Kawasaki has stated that location is not the only deciding factor in determining origin.

“The evolutionary relationship of genes can usually be detected when two genes retain similar nucleotide sequences or encoded amino acid sequences,” Kawasaki said, referring to the materials that make up an organism’s genetic code. “But previous studies could not detect any genes with sequence similarities to the J-chain gene, probably because the sequence of the J-chain gene was rapidly changed at its origin.”

Flajnik said he had a hunch that the J chain was related to a group of calcium-binding phosphoprotein (SCPP) secretory genes because of their similar charges and levels of the amino acid proline. He knew Kawasaki was an expert on SCPP genes, so he emailed him to evaluate the idea.

“He told me that, for various good reasons, SCPP and Channel J were not related,” Flajnik said. “It was sad, because that was my favorite hypothesis.”

However, Kawasaki had noticed that genes on the opposite side of the J chain, away from the SCPP genes, appeared to be related to the J chain. These were the CXCL chemokine genes.

“I immediately checked these CXCL chemokine genes and found that although these genes do not have sequence similarities with J-chain genes, these genes and the J-chain gene resemble each other with various characteristics,” Kawasaki said.

These features include the same number of exons, which code for the protein, and intron frames, which act as switches to stop or start the splicing of RNA molecules transcribed from the gene. The second exon encodes the same sequence for both genes, known as the classic cysteine-X-cysteine ​​tripeptide. The lengths of three of the exons are also similar.

“No other gene encoding the human secretome, which encompasses all proteins that can be secreted by an organism’s cells, shares these three characteristics,” Kawasaki said.

The connections between the cysteine ​​molecules encoded by the second exon of each gene, however, are completely different from each other, the researchers said.

“This means that a chemokine can change its structure to a large extent and take on a new function,” Flajnik said.

Next, the researchers said they plan to investigate whether chemokines have taken on other functions, particularly in the immune system. They also want to study whether the structure of chemokines is flexible, which could indicate their ability to adopt an entirely new secondary structure, adapting in response to different biological needs, as needed.

“I’ve been working in science for a long time, 44 years, but this experience has been one of the most incredibly satisfying and fortunate,” Flajnik said. “I doubt this similarity would have been discovered long ago if not for the chance interaction between Kazuhiko and me.”