Biology subjects

Oka, M.

Publications and source records attributed to Oka, M..

8 recordsLinked to original sources

bioRxiv2024

Glucose uptake in pigment glia suppresses tau-induced inflammation and photoreceptor degeneration in Drosophila

Brain inflammation contributes to the pathogenesis of neurodegenerative diseases such as Alzheimers disease (AD). Glucose hypometabolism and glial activation are pathological features seen in AD brains; however, the connection between the two is not fully understood. Using a Drosophila model of AD, we identified that glucose metabolism in glia plays a critical role in neuroinflammation under disease conditions. Expression of human Tau in the retinal cells, including photoreceptor neurons and pigment glia, causes photoreceptor degeneration accompanied by inclusion formation and swelling of the lamina cortex. We found that inclusions are formed by glial phagocytosis, and swelling of the laminal cortex correlates with the expression of antimicrobial peptides. Co-expression of human glucose transporter 3 (GLUT3) with Tau in the retina does not affect tau levels but suppresses these inflammatory responses and photoreceptor degeneration. We also found that expression of GLUT3, specifically in the pigment glia, is sufficient to suppress inflammatory phenotypes and mitigate photoreceptor degeneration in the tau-expressing retina. Our results suggest that glial glucose metabolism contributes to inflammatory responses and neurodegeneration in tauopathy. Summary StatementGlucose uptake into pigment glia suppresses inflammatory responses and photoreceptor degeneration in the fly model of tauopathy.

neuroscience↗

bioRxiv2024

Importin α4 deficiency induces psychiatric disorder-related behavioral deficits and neuroinflammation in mice.

Importin 4, which is encoded by the Kpna4 gene, is a well characterized nuclear-cytoplasmic transport factor known to mediate transport of transcription factors including NF-{kappa}B. Here, we report that Kpna4 knock-out (KO) mice exhibit psychiatric disorder-related behavioral abnormalities such as anxiety-related behaviors, deceased social interaction and sensorimotor gating deficits. Contrary to a previous study predicting attenuated NF-{kappa}B activity as a result of Kpna4 deficiency, we observed a significant increase in expression levels of NF-{kappa}B genes and pro-inflammatory cytokines such as TNF, Il1{beta} or Il-6 in the Prefrontal Cortex or Basolateral Amygdala of the KO mice. Moreover, examination of inflammatory responses in primary cells revealed that Kpna4 deficient cells have an increased inflammatory response, which was rescued by addition of not only full-length, but also a nuclear transport deficient truncation mutant of importin 4, suggesting contribution of its non-transport functions. Furthermore, RNAseq of sorted adult Microglia and Astrocytes and subsequent transcription factor analysis suggested increases in Polycomb repressor complex 2 (PRC2) activity in Kpna4 KO cells. Taken together, importin 4 deficiency induces psychiatric disorder-related behavioral deficits in mice, along with an increased inflammatory response and possible alteration of PRC2 activity in glial cells.

neuroscience↗

bioRxiv2023

Importin-7-dependent nuclear localization of the Flavivirus core protein is required for infectious virus production.

Flaviviridae is a family of positive-stranded RNA viruses, including human pathogens such as Japanese encephalitis virus (JEV), dengue virus (DENV), zika virus (ZIKV), and West Nile virus (WNV). Nuclear localization of the viral core protein is conserved among Flaviviridae, and this feature may be targeted for developing broad-ranging anti-flavivirus drugs. However, the mechanism of core protein translocation to the nucleus and the importance of nuclear localization in the viral life cycle remain unknown. We aimed to identify the molecular mechanism underlying core protein nuclear translocation. We identified importin-7 (IPO7), an importin-{beta} family protein, as a nuclear carrier for Flaviviridae core proteins. Nuclear import assays revealed that core protein was transported into the nucleus via IPO7, whereas IPO7 deletion by CRISPR/Cas9 impaired their nuclear localization. To understand the importance of core protein nuclear localization, we evaluated the production of infectious virus or single-round-infectious-particles in wild-type or IPO7-deficient cells; both processes were significantly impaired in IPO7-deficient cells, whereas intracellular infectious virus levels were equivalent in wild-type and IPO7-deficient cells. These data suggested that IPO7-mediated nuclear localization of core proteins plays a role in the release of infectious virus particles of flaviviruses.

microbiology↗

bioRxiv2023

Importin α as a molecular marker for investigating the microenvironment of micronuclei

Micronuclei (MN) are membrane-enclosed chromatin bodies and hallmarks of genome instability. Here, we report that importin , a key nuclear transport factor, is highly concentrated in a distinct subset of MN in cultured human cancer cells. This selective localization is not governed by classical nuclear transport pathways. Live-cell photobleaching revealed remarkably reduced mobility of importin between MN and cytoplasm. In addition, the subset of importin -positive MN exhibited collapsed nuclear envelopes and compromised barrier functions. Importin was also enriched in euchromatin regions, where it colocalized with chromatin-regulating molecules. Importantly, importin and DNA repair/sensing molecules such as RAD51, RPA2, and cGAS showed mutually exclusive localization in MN, indicating that MN comprise distinct internal environments. These findings identify importin as a molecular marker of the restricted MN state, representing a previously unrecognized microenvironment distinct from subsets characterized by conventional molecular markers of disrupted MN. This framework provides new insights into how MN heterogeneity underlies genome instability and immune evasion during cancer progression. Summary statementAccumulation of importin in micronuclei, followed by modulation of the microenvironment of the micronuclei, suggests a non-canonical function of importin in genomic instability and cancer development.

cell biology↗

bioRxiv2022

Phase-separated nuclear bodies of nucleoporin fusions, SET-NUP214 and NUP98-HOXA9, promote condensation of MLL1 and CRM1 to activate target genes

Nucleoporins NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies. However, the function and physiological significance of these nuclear bodies remain largely unknown. Previously, we reported that both NUP98-HOXA9 and SET-NUP214 are recruited to HOX cluster regions via chromatin-bound CRM1, a nuclear export receptor (Oka et al., 2019). Here, we show that these nuclear bodies promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase which is essential for the maintenance of HOX gene expression. Our analysis revealed that SET-NUP214 and CRM1 robustly associate with MLL1 to form nuclear bodies and are colocalized on chromatin. We also showed that MLL1 and CRM1 are recruited to the nuclear bodies of NUP98-HOXA9 and that the NUP98-HOXA9/CRM1/MLL1 complex accumulates on its target gene loci, including HOX clusters and MEIS1. These phenomena were not observed in phase-separation-deficient mutants or non-DNA-binding mutants of NUP98-HOXA9. Collectively, these results show that both phase separation and proper targeting of nucleoporin fusions to specific sites could enhance the activation of a wide range of target genes by promoting the condensation of MLL1 and CRM1.

cell biology↗

bioRxiv2021

SARS-CoV-2 ORF6 disturbs nucleocytoplasmic trafficking to advance the viral replication

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the coronavirus disease 2019 pandemic. ORF6 is known to antagonize the interferon signaling by inhibiting the nuclear translocation of STAT1. Here we show that ORF6 acts as a virulence factor through two distinct strategies. First, ORF6 directly interacts with STAT1 in an IFN-independent manner to inhibit its nuclear translocation. Second, ORF6 directly binds to importin 1, which is a nuclear transport factor encoded by KPNA2, leading to a significant suppression of importin 1-mediated nuclear transport. Furthermore, we found that KPNA2 knockout enhances the viral replication, suggesting that importin 1 suppresses the viral propagation. Additionally, the analyses of gene expression data revealed that importin 1 levels decreased significantly in the lungs of older individuals. Taken together, SARS-CoV-2 ORF6 disrupts the nucleocytoplasmic trafficking to accelerate the viral replication, resulting in the disease progression, especially in older individuals.

microbiology↗

bioRxiv2020

Increasing glucose uptake into neurons antagonizes brain aging and promotes health and life span under dietary restriction in Drosophila

Brain neurons play a central role in organismal aging, but there is conflicting evidence about the roles of neuronal glucose availability, glucose uptake and metabolism in aging and extended lifespan. Here, we analyzed metabolic changes in the brain neurons of Drosophila during aging. Using a genetically-encoded fluorescent ATP biosensor, we found decreased ATP concentration in the neuronal somata of aged flies, which was correlated with decreased glucose content, expression of glucose transporter and glycolytic enzymes and mitochondrial quality. The age-associated reduction in ATP concentration did not occur in brain neurons with suppressed glycolysis or enhanced glucose uptake, suggesting these pathways contribute to reductions in ATP. Despite age-associated mitochondrial damage, increasing glucose uptake maintained ATP levels, suppressed age-dependent locomotor deficits and extended the life span. Increasing neuronal glucose uptake during dietary restriction resulted in the longest lifespans, suggesting an additive effect of enhancing glucose availability during a bioenergetic challenge on aging.

neuroscience↗

bioRxiv2018

miR-10b Deficiency Affords Atherosclerosis Resistance

Human vascular endothelial cells (ECs) are categorized into two groups; pro-stenotic (Type-I) and anti-stenotic (Type-II) ECs, and one of the master genes for a stress-induced \"Type-II-to-Type-I\" degeneration is Regulator of G-protein signaling 5 (RGS5). Here we show that miR-10b is a crucial downstream mediator in RGS5-dependent degeneration. We also demonstrated the miR-10bhigh Type-I EC exosome has a trans effect which suppresses anti-proliferative abilities of Type-II ECs. Moreover, we found miR-10b-deficient mice showed a resistance to experimental atherosclerosis, where high-fat-high-cholesterol-diet-fed mice were subjected to partial carotid ligation. Furthermore, we determined the key target of miR-10b was Latent transforming growth factor-{beta} binding protein 1 (LTBP1), which is a regulator of TGF-{beta} signaling. Compatible with a commonly accepted view that TGF-{beta} creates the major growth-inhibitory signal against vascular smooth muscle cells, TGF-{beta} inhibitor treatments abolished anti-proliferative functions of Type-II ECs. Therefore, RGS5/miR-10b/LTBP1/TGF-{beta} axis plays a leading role in quality control of ECs.

cell biology↗