Biology subjects

Irie, M.

Publications and source records attributed to Irie, M..

4 recordsLinked to original sources

bioRxiv2026

A eutherian-specific metaviral gene, RTL6, coordinates microglial inflammatory responsiveness and state regulation

RTL6 (also known as SIRH3) is a eutherian-specific metavirus-derived gene highly conserved among placental mammals. We previously demonstrated that RTL6 is expressed in microglia and secreted into the brain extracellular space, where it mediates the trapping and clearance of bacterial lipopolysaccharide (LPS). However, its role in microglial TLR4 signaling remained unclear. To investigate the earliest LPS response, we performed RNA-seq analysis of wild-type and Rtl6-deficient primary microglia following 10 min of LPS stimulation. Rtl6-deficient microglia exhibited compensatory upregulation of residual transcripts derived from the untranslated region of Rtl6, suggesting feedback regulation of Rtl6 expression. Loss of RTL6 attenuated the induction of immediate-early response genes, including Fos, Jun, Nr4a1, Nr4a2, Egr2, and Egr3, together with broad suppression of interferon-responsive and inflammatory transcriptional programs. Altered neuronal and oligodendrocyte/myelin interaction pathways indicated remodeling of microglial communication networks. Strikingly, genes involved in cell-cycle progression, DNA replication, chromatin assembly, DNA repair, and genome maintenance were coordinately upregulated, including multiple disease-associated microglia (DAM)-related genes. Collectively, these findings indicate that RTL6 couples extracellular LPS sensing to inflammatory transcriptional responses while regulating microglial functional state transitions. Our results identify RTL6 as a previously unrecognized component of the regulatory network governing microglial functional states in placental mammals.

molecular biology↗

bioRxiv2024

RTL4, a retrovirus-derived gene implicated in autism spectrum disorder, is a microglial gene that responds to noradrenaline in the postnatal brain

RTL4, a gene acquired from a retrovirus, is a causative gene in autism spectrum disorder. Its KO mice exhibit increased impulsivity, impaired short-term spatial memory, failure to adapt to novel environments, and delayed noradrenaline (NA) recovery in the frontal cortex. However, due to its very low expression in the brain, it remains unknown which brain cells express RTL4 and its dynamics in relation to NA. Here, using knock-in mice carrying endogenous Rtl4 fused to Venus, we demonstrated that RTL4 is a microglial gene with several important properties. The RTL4-Venus fusion protein was detected as a secreted protein in the midbrain, hypothalamus, hippocampus and amygdala in the postnatal brain. Its signal intensity was high during critical periods of neonatal adaptation to novel environments and was upregulated by various stimuli, such as handling the mice, mild environmental changes and administration of isoproterenol, an agonist of adrenergic beta receptors. It was decreased by anesthesia but was maintained by the administration of milnacipran, an NA reuptake inhibitor. These results suggest that RTL4 intensity depends on the arousal state via NA and is somehow related to the NA reuptake process. In vitro mixed glial culture experiments demonstrated that Rtl4 is a microglial gene and suggested that RTL4 secretion responds rapidly to isoproterenol. Taken together with previous results from Rtl4 KO mice, microglial RTL4 plays an important role in the NA response and it is likely involved in the development of the NAergic neuronal network in the brain.

molecular biology↗

bioRxiv2023

Retrovirus-derived RTL9 plays an important role in innate antifungal immunity in the eutherian brain

Retrotransposon Gag-like (RTL) genes plays a variety of essential/important roles in the eutherian placenta and brain. It has recently been demonstrated that RTL5 and RTL6 (aka sushi-ichi retrotransposon homolog 8 (SIRH8) and SIRH3) are microglial genes that play important roles in the brains innate immunity against viruses and bacteria by their removal of double-stranded RNA and lipopolysaccharide, respectively. Here we demonstrate that RTL9 (aka SIRH10) also plays an important role, degrading fungal zymosan in the brain. The RTL9 protein is localized in the microglial lysosomes where incorporated zymosan is digested. Interestingly, in Rtl9 knockout mice expressing RTL9{Delta}C protein lacking the C-terminus retroviral GAG-like region, the zymosan degrading activity was lost, demonstrating that RTL9 is essentially engaged in this reaction, presumably via its GAG-like region. Together with our previous study, this result highlights the importance of three retrovirus-derived microglial RTL genes as eutherian-specific constituents of the current brain innate immune system, RTL9, RTL5 and RTL6 responding to fungi, viruses and bacteria, respectively. Author SummaryWe have recently demonstrated that RTL5 and RTL6 are microglial genes that play important roles in the brains innate immunity against viruses and bacteria. In this report, we demonstrate that RTL9 is functional in innate antifungal immunity in the brain because Rtl9 KO mice lose zymosan degradation activity. Fungi are one of the most dangerous infectious pathogens, along with viruses, bacteria and protozoa. Phagocytic cells, such as microglia/macrophages, are essential for mounting a defense against fungal infection. As defects in these cells reduce host resistance to fungal infection, RTL9 is an antifungal therapy target as a newly identified member of innate antifungal immunity in eutherians.

evolutionary biology↗

bioRxiv2021

Retrovirus-derived acquired genes, RTL5 and RTL6, are novel constituents of the innate immune system in the eutherian brain.

Retrotransposon Gag-like 5 (RTL5, also known as sushi-ichi-related retrotransposon homolog 8 (SIRH8)) and RTL6 (aka SIRH3) are eutherian-specific genes presumably derived from a retrovirus and phylogenetically related to each other. RTL5 encodes a strongly acidic protein while RTL6 encodes an extremely basic protein, and the former is well conserved and the latter extremely well conserved among the eutherians, indicating their unique and critically important roles as acquired genes. Here we report that RTL5 and RTL6 are microglial genes playing roles in the front line of brain innate immune responses against distinct pathogens. Venus and mCherry knock-in mice exhibited expression of RTL5-mCherry and RTL6-Venus fusion proteins in microglia and as extracellular granules in the central nervus system (CNS), and displayed a rapid response to pathogens such as lipopolysaccharide (LPS), double-stranded (ds) RNA analog and non-methylated CpG DNA. These proteins trapped pathogens in microglia in a variety of RTL-pathogen complexes depending on the pathogens. These results demonstrate that RTL5 and RTL6 exert functional effects against different hazardous substances cooperatively and/or independently to protect the developing and/or mature brain. This provides the first evidence that retrovirus-derived genes play a role in the innate immune system of the eutherian brain.

evolutionary biology↗