Biology subjects

Kirino, Y.

Publications and source records attributed to Kirino, Y..

6 recordsLinked to original sources

bioRxiv2026

RIPK3-RNASE1 axis as a potential therapeutic and clinical monitoring target in VEXAS syndrome

Vacuole, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome (VS) is a severe autoinflammatory disease driven by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), for which disease activity biomarkers and therapeutic targets are needed. We conducted longitudinal deep phenotyping of patients with VS and found that ribonuclease 1 (RNASE1) expression is most strongly correlated with the disease activity score measured by the VEXAS Current Activity Form (VEXASCAF). Single-cell RNA-sequencing showed that RNASE1 was upregulated in VS monocytes. We generated human monocytic cell lines harboring UBA1 mutations (p.Met41Val, p.Met41Leu, and p.Met41Thr). These cells exhibited varying degrees of impaired ubiquitination and subsequent pathological features such as the unfolded protein response, increased pro-inflammatory cytokine production, cell death, and RNASE1 expression, mirroring the genotype-phenotype associations observed in patients with VS. Multi-omics analyses revealed that genotypes linked to greater clinical severity were enriched in pro-inflammatory, interferon, and necroptosis signatures. Notably, functional interrogation demonstrated that inhibition of receptor-interacting protein kinase 3 (RIPK3), a key regulator of necroptosis, markedly suppressed all these pathological features, including the elevated RNASE1 expression. These results identify the RIPK3-RNASE1 axis in VS, highlighting RNASE1 as a potential biomarker and RIPK3 as an attractive therapeutic target.

immunology↗

bioRxiv2024

Immunoactive signatures of circulating tRNA- and rRNA-derived RNAs in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is the most prevalent lung disease, and macrophages play a central role in the inflammatory response in COPD. We here report a comprehensive characterization of circulating short non-coding RNAs (sncRNAs) in plasma from patients with COPD. While circulating sncRNAs are increasingly recognized for their regulatory roles and biomarker potential in various diseases, the conventional RNA-seq method cannot fully capture these circulating sncRNAs due to their heterogeneous terminal structures. By pre-treating the plasma RNAs with T4 polynucleotide kinase, which converts all RNAs to those with RNA-seq susceptible ends (5'-phosphate and 3'-hydroxyl), we comprehensively sequenced a wide variety of non-microRNA sncRNAs, such as 5'-tRNA halves containing a 2',3'-cyclic phosphate. We discovered a remarkable accumulation of the 5'-half derived from tRNAValCACin plasma from COPD patients, whereas the 5'-tRNAGlyGCChalf is predominant in healthy donors. Further, the 5'-tRNAValCAChalf activates human macrophages via Toll-like receptor 7 and induces cytokine production. Additionally, we identified circulating rRNA-derived fragments that were upregulated in COPD patients and demonstrated their ability to induce cytokine production in macrophages. Our findings provide evidence of circulating, immune-active sncRNAs in patients with COPD, suggesting that they serve as inflammatory mediators in the pathogenesis of COPD.

molecular biology↗

bioRxiv2021

SIPA1L1/SPAR1 is a non-PSD protein involved in GPCR signaling

SIPA1L1 (also known as SPAR1) has been proposed to regulate synaptic functions that are important in maintaining normal neuronal activities, such as regulating spine growth and synaptic scaling, as a component of the postsynaptic density (PSD)-95/N-methyl-D-aspartate receptor (NMDA-R)-complex. However, contrary to this view, our super-resolution and immunoelectron microscopic analyses demonstrate that SIPA1L1 is mainly localized to general submembranous and cytoplasmic regions in neurons, but scarcely to PSD. Our screening for native interactors of SIPA1L1 identified spinophilin and neurabin-1, regulators of G protein-coupled receptor (GPCR) signaling, but rejected PSD-95/NMDA-R-complex components. Furthermore, Sipa1l1-/- mice showed normal spine size distribution and NMDA-R-dependent synaptic plasticity. Nevertheless, Sipa1l1-/- mice showed aberrant responses to 2-adrenergic receptor (a spinophilin target) or adenosine A1 receptor (a neurabin-1 target) agonist stimulation and striking behavioral anomalies, such as hyperactivity, enhanced anxiety, learning impairments, social interaction deficits, and enhanced epileptic seizure susceptibility. Our findings revealed unexpected properties of SIPA1L1, suggesting a possible association of SIPA1L1 deficiency with neuropsychiatric disorders related to dysregulated GPCR signaling, such as epilepsy, attention deficit hyperactivity disorder (ADHD), autism, or fragile X syndrome.

neuroscience↗

bioRxiv2019

Allergen-induced tRNA halves repress focal adhesion of airway smooth muscle cells

The RNase A superfamily, one of the most extensively studied enzyme families, remains incompletely defined with respect to its endogenous RNA substrates, recognition mechanisms, and physiological functions. Here, we identify eosinophil-derived neurotoxin (EDN/RNase 2) as a principal endoribonuclease mediating tRNA cleavage in the asthmatic lung. Inhalation of house dust mite (HDM) in mice induces robust accumulation of tRNA halves in the lung, coinciding with exclusive upregulation of EDN, but not other ribonucleases. In human lung epithelial cells, internalized EDN cleaves specific tRNAs and generates multiple species of tRNA halves, including immunostimulatory species that activate Toll-like receptor 7 (TLR7). EDN also promotes the release of extracellular vesicles enriched in these RNAs, implicating them in cytokine production during asthma pathogenesis. Biochemical analyses and structural simulations reveal that EDN recognizes the anticodon loop of tRNA by anchoring the phosphate backbones flanking the cleavage site, thereby precisely positioning the C34-A35 phosphodiester bond for catalysis. Furthermore, the highly efficient cleavage by EDN is mediated by conserved elements, including Arg36 in EDN and U33 and C38 in the target tRNA. Together, these findings establish the endogenous RNA substrate of EDN and uncover a molecular mechanism that links RNase A superfamily activity to immune response.

molecular biology↗

bioRxiv2019

Structural studies of the Tudor domain from the Bombyx homolog of Drosophila PAPI: Implication to piRNA biogenesis

PIWI proteins and their associated PIWI-interacting RNAs (piRNAs) play crucial roles in proper gametogenesis in animal gonads. Partner of PIWIs (PAPI) is one of the important piRNA biogenesis factors. PAPI contains a Tudor domain and tandem KH domains. The tudor domain specifically recognizes symmetrical-dimethylarginines (sDMAs) on PIWI proteins. BmPAPI, a Bombyx mori homolog of PAPI, is localized at the outer membrane of mitochondria and supports exonucleolytic trimming of piRNA precursors to form mature 3-end of piRNAs. To understand the structural basis of piRNA processing by BmPAPI, we present crystal structures of the apo- and sDMA-liganded Tudor domain of BmPAPI.

biophysics↗

bioRxiv2017

Systems-Level Analysis Of 32 TCGA Cancers Reveals Disease-Dependent tRNA Fragmentation Patterns And Very Selective Associations With Messenger RNAs And Repeat Elements

We mined 10,274 datasets from The Cancer Genome Atlas (TCGA) for tRNA fragments (tRFs) that overlap nuclear and mitochondrial (MT) mature tRNAs. Across 32 cancer types, we identified 20,722 distinct tRFs, a third of which arise from MT tRNAs. Most of the fragments belong to the novel category of i-tRFs, i.e. they are wholly internal to the mature tRNAs. The abundances and cleavage patterns of the identified tRFs depend strongly on cancer type. Of note, in all 32 cancer types, we find that tRNAHisGTG produces multiple and abundant 5{acute}-tRFs with a uracil at the -1 position, instead of the expected post-transcriptionally-added guanosine. Strikingly, these -1U His 5{acute}tRFs are produced in ratios that remain constant across all analyzed normal and cancer samples, a property that makes tRNAHisGTG unique among all tRNAs. We also found numerous tRFs to be negatively correlated with many messenger RNAs (mRNAs) that belong primarily to four universal biological processes: transcription, cell adhesion, chromatin organization and development/morphogenesis. However, the identities of the mRNAs that belong to these processes and are negatively correlated with tRFs differ from cancer to cancer. Notably, the protein products of these mRNAs localize to specific cellular compartments, and do so in a cancer-dependent manner. Moreover, the genomic span of mRNAs that are negatively correlated with tRFs are enriched in multiple categories of repeat elements. Conversely, the genomic span of mRNAs that are positively correlated with tRFs are depleted in repeat elements. These findings suggest novel and far-reaching roles for tRFs and indicate their involvement in system-wide interconnections in the cell. All discovered tRFs from TCGA can be downloaded from https://cm.jefferson.edu/tcga-mintmap-profiles or studied interactively through the newly-designed version 2.0 of MINTbase at https://cm.jefferson.edu/MINTbase.\n\nNOTE: while the manuscript is under review, the content on the page https://cm.jefferson.edu/tcgamintmap-profiles is password protected and available only to Reviewers.\n\nKey PointsO_LIComplexity: tRNAs exhibit a complex fragmentation pattern into a multitude of tRFs that are conserved within the samples of a given cancer but differ across cancers.\nC_LIO_LIVery extensive mitochondrial contributions: the 22 tRNAs of the mitochondrion (MT) contribute 1/3rd of all tRFs found across cancers, a disproportionately high number compared to the tRFs from the 610 nuclear tRNAs.\nC_LIO_LIUridylated (not guanylated) 5{acute}-His tRFs: in all human tissues analyzed, tRNAHisGTG produces many abundant modified 5{acute}-tRFs with a U at their \"-1\" position (-1U 5{acute}-tRFs), instead of a G.\nC_LIO_LILikely central roles for tRNAHisGTG: the relative abundances of the -1U 5{acute}-tRFs from tRNAHisGTG remain strikingly conserved across the 32 cancers, a property that makes tRNAHisGTG unique among all tRNAs and isoacceptors.\nC_LIO_LISelective tRF-mRNA networks: tRFs are negatively correlated with mRNAs that differ characteristically from cancer to cancer.\nC_LIO_LIMitochondrion-encoded tRFs are associated with nuclear proteins: in nearly all cancers, and in a cancer-specific manner, tRFs produced by the 22 mitochondrial tRNAs are negatively correlated with mRNAs whose protein products localize to the nucleus.\nC_LIO_LItRFs are associated with membrane proteins: in all cancers, and in a cancer-specific manner, nucleus-encoded and MT-encoded tRFs are negatively correlated with mRNAs whose protein products localize to the cells membrane.\nC_LIO_LItRFs are associated with secreted proteins: in all cancers, and in a cancer-specific manner, nucleusencoded and MT-encoded tRFs are negatively correlated with mRNAs whose protein products are secreted from the cell.\nC_LIO_LItRFs are associated with numerous mRNAs through repeat elements: in all cancers, and in a cancerspecific manner, the genomic span of mRNAs that are negatively correlated with tRFs are enriched in specific categories of repeat elements.\nC_LIO_LIintra-cancer tRF networks can depend on sex and population origin: within a cancer, positive and negative tRF-tRF correlations can be modulated by patient attributes such as sex and population origin.\nC_LIO_LIweb-enabled exploration of an \"Atlas for tRFs\": we released a new version of MINTbase to provide users with the ability to study 26,531 tRFs compiled by mining 11,719 public datasets (TCGA and other sources).\nC_LI

systems biology↗