Innate immunity responds by pathogen mutation-defined signaling pathways in infected cells with disease and even cancer. Deficient signaling weakens the response to infection while overreacting responses toward infection result in aberrant inflammatory diseases and several autoimmune diseases. These, therefore, are reduced signaling pathways, the regulation of which is known to very little in general about their respective ways of regulation.
Although almost mammalian immunity signaling seems conserved, their responses, however, within and between species vary, suggesting the fact that these species exhibit a species-concerning mechanism for that difference in immune regulation and functions. These efforts, then, are beginning to elucidate the mechanisms. However, the discovery of their molecular bases will be key to understanding and consequently treating immune-mediated diseases.
A study done by CU Boulder published in Cell informs about what the authors term an “immune system tuning dial” that evolved as a bug of the genetic code tens of millions of years ago and found that there is a whole class of underappreciated protein variants that can hugely affect our immune function, according to Ed Chuong, senior author and assistant professor in the Department of Molecular, Cellular and Developmental Biology and the Bio Frontiers Institute.
Chuong examines transposons, pieces of DNA that, following infiltration into primate cells more than 70 million years ago, now makeup over half of the human genome. Some transposons, called endogenous retroviruses, got there through ancient viruses, while others–like those being examined in the current paper–erupted from the genome itself like haphazard bugs in a program’s source code. Renewed, genetic parasites are said to help cancer survive and thrive.
A transposon-the explanation by the first author Giulia Pasquesi, postdoc under Chuong-plays the same role as a noun in a sentence: If you think of a gene as a sentence, a transposon makes that word jump into the sentence, slightly altering how the instructions for the cell are delivered. Cells usually don’t express these bugs; they make sure that only the correct version of the gene is activated; hence scientists view these as inert “junk DNA.” In seeking out his “truth,” Pasquesi challenged such assumptions and set about hunting for gene variants induced by transposons, which could play rather a significant role in conferring human immunity. When analyzing the cutting-edge genetic sequencing data from human tissues and cells, she found 125 occurrences across 99 genes.
To investigate the role of TE exonization in the development of transcript isoforms of immune-related genes, researchers analyzed the long-read transcriptomic datasets from macrophages and healthy human tissues that were obtained through the genotype-tissue expression (GTEx) project. Using long-read transcriptome assemblies, researchers identified isoforms of protein-coding genes that included at least one exonized TE and demonstrated significant expression levels (measured as transcripts per million, TPM ≥ 5) in at least one sample. The study revealed 3,503 exonization events across 5,991 isoforms from 2,707 unique genes in the GTEx human tissue panel and 1,230 exonization events within 1,878 isoforms from 1,045 genes in the macrophage dataset. The findings revealed that SINE TEs, particularly Alu elements were the most main class to undergo exonization, whether inserted in the same (sense) or opposite (antisense) orientation relative to the protein-coding gene which is followed by LINEs and long terminal repeat (LTR) or DNA elements.
After they had finished laboratory studies at different combinations of the two versions of IFNAR2 on cells, they subjected them to immune challenges, for example, viral infections, and discovered that the short variant acted as a decoy into the channel obstructing normal signaling with IFNAR2. The short variant has been removed from the genome, and most cells became highly sensitive to interferon, thus responding with enhanced immunity against viruses like SARS-CoV-2 and dengue. Hence, it provides that the balance among IFNAR2 can be regarded as the “tuning dial” for the immune signaling strength that varies from individual to individual. Individuals presenting abnormally high levels of the variant may develop more vulnerability toward more severe infections, while others expressing lower levels may suffer from chronic inflammations.
Reference: Giulia Irene Maria Pasquesi et al, Regulation of human interferon signaling by transposon exonization, Cell (2024). DOI:10.1016/j.cell.2024.11.016
