担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbadva.2025.100144

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.isci.2024.111457

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fimmu.2024.1475473

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.antiviral.2024.106040

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Differentiation therapy is an alternative strategy used in treating chronic myelogenous leukemia (CML) to induce the differentiation of immature or cancerous cells towards mature cells and inhibit tumor cell proliferation. We aimed to explore N-glycans' roles in erythroid differentiation using the sodium butyrate (NaBu)-induced model of K562 cells (WT/NaBu cells). Here, using lectin blot, flow cytometry, real-time PCR, and mass spectrometry analyses, we demonstrated that the mRNA levels of N-acetylglucosaminyltransferase Ⅲ (GnT-Ⅲ encoded by the MGAT3 gene) and its product (bisected N-glycans) were significantly increased during erythroid differentiation. To address the importance of GnT-Ⅲ in this progress, we established a stable MGAT3 knockout (KO) K562 cell line using the CRISPR/Cas9 technology. Compared to WT/NaBu cells, MGAT3 KO significantly impeded the progression of erythroid differentiation, as shown in decreased cell color and levels of erythroid markers, glycophorin A (CD235a), and β-globin. Consistently, MGAT3 KO mitigated the inhibitory impact of NaBu on cell proliferation. During induction, MGAT3 KO suppressed the cellular phosphorylated tyrosine and phospho-ERK1/2 levels. Inhibition of the ERK/MAPK signaling pathway using U0126 blocked erythroid differentiation while concurrently suppressing the expression levels of MGAT3 and bisected N-glycans. Furthermore, the lack of bisecting GlcNAc modification on c-Kit and transferrin receptor 1 (CD71) suppressed cellular signaling and accelerated the degradation of the CD71 protein, respectively. Our study highlights the critical role of MGAT3 in regulating erythroid differentiation associated with the ERK/MAPK signaling pathway, which may shed light on identifying new differentiation therapy in chronic myelogenous leukemia.

DOI： 10.1016/j.jbc.2024.108010

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/glycob/cwae052

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12891-024-07704-7

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Presenilin proteins (PS1 and PS2) represent the catalytic subunit of γ-secretase and play a critical role in the generation of the amyloid β (Aβ) peptide and the pathogenesis of Alzheimer disease (AD). However, PS proteins also exert multiple functions beyond Aβ generation. In this study, we examine the individual roles of PS1 and PS2 in cellular cholesterol metabolism. Deletion of PS1 or PS2 in mouse models led to cholesterol accumulation in cerebral neurons. Cholesterol accumulation was also observed in the lysosomes of embryonic fibroblasts from Psen1-knockout (PS1-KO) and Psen2-KO (PS2-KO) mice and was associated with decreased expression of the Niemann-Pick type C1 (NPC1) protein involved in intracellular cholesterol transport in late endosomal/lysosomal compartments. Mass spectrometry and complementary biochemical analyses also revealed abnormal N-glycosylation of NPC1 and several other membrane proteins in PS1-KO and PS2-KO cells. Interestingly, pharmacological inhibition of N-glycosylation resulted in intracellular cholesterol accumulation prominently in lysosomes and decreased NPC1, thereby resembling the changes in PS1-KO and PS2-KO cells. In turn, treatment of PS1-KO and PS2-KO mouse embryonic fibroblasts (MEFs) with the chaperone inducer arimoclomol partially normalized NPC1 expression and rescued lysosomal cholesterol accumulation. Additionally, the intracellular cholesterol accumulation in PS1-KO and PS2-KO MEFs was prevented by overexpression of NPC1. Collectively, these data indicate that a loss of PS function results in impaired protein N-glycosylation, which eventually causes decreased expression of NPC1 and intracellular cholesterol accumulation. This mechanism could contribute to the neurodegeneration observed in PS KO mice and potentially to the pathogenesis of AD.

DOI： 10.3390/ijms25105417

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.7554/eLife.92275

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2024.149610

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41419-024-06432-z

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fnins.2024.1437668

PubMed

担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

J-GLOBAL

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ymgmr.2023.101016

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sialylation is a terminal glycosylated modification of glycoproteins that regulates critical biological events such as cell adhesion and immune response. Our previous study showed that integrin α3β1 plays a crucial role in regulating the sialylation of N-glycans. However, the underlying mechanism for the regulation remains unclear. This study investigated how sialylation is affected by focal adhesion kinase (FAK), which is a critical downstream signal molecule of integrin β1. We established a stable focal adhesion kinase (FAK) knockout (KO) cell line using the CRISPR/Cas9 system in HeLa cells. The results obtained from lectin blot, flow cytometric analysis, and mass spectrometry (MS) showed that the sialylation levels were significantly decreased in the KO cells compared with that in wild-type (WT) cells. Moreover, phosphatidylinositol 4-phosphate (PI4P) expression levels were also reduced in the KO cells due to a decrease in the stability of phosphatidylinositol 4-kinase-IIα (PI4KIIα). Notably, the decreased levels of sialylation, PI4P, and the complex formation between GOLPH3 and ST3GAL4 or ST6GAL1, which are the main sialyltransferases for modification of N-glycans, were significantly restored by the re-expression of FAK. Furthermore, the decreased sialylation and phosphorylation of Akt and cell migration caused by FAK deficiency all were restored by overexpressing PI4KIIα, which suggests that PI4KIIα is one of the downstream molecules of FAK. These findings indicate that FAK regulates sialylation via the PI4P synthesis pathway and a novel mechanism is suggested for the integrin-FAK-PI4KIIα-GOLPH3-ST axis modulation of sialylation in N-glycans.

DOI： 10.1016/j.jbc.2023.105051

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10719-023-10109-8

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbagen.2023.130331

PubMed

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/978-1-0716-2910-9_21

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.chroma.2022.463748

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： DOI: 10.2217/rme-2022-0010

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： https://doi.org/10.3390/ijms232113097

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：論文集(書籍)内論文  

DOI： DOI: 10.1007/978-1-0716-2635-1_1

記述言語：日本語   出版者・発行元：Scientific Reports  

Podocytopathy, which is characterized by injury to podocytes, frequently causes proteinuria or nephrotic syndrome. There is currently a paucity of effective therapeutic drugs to treat proteinuric kidney disease. Recent research suggests the possibility that glycosphingolipid GM3 maintains podocyte function by acting on various molecules including nephrin, but its mechanism of action remains unknown. Here, various analyses were performed to examine the potential relationship between GM3 and nephrin, and the function of GM3 in podocytes using podocytopathy mice, GM3 synthase gene knockout mice, and nephrin injury cells. Reduced amounts of GM3 and nephrin were observed in podocytopathy mice. Intriguingly, this reduction of GM3 and nephrin, as well as albuminuria, were inhibited by administration of valproic acid. However, when the same experiment was performed using GM3 synthase gene knockout mice, valproic acid administration did not inhibit albuminuria. Equivalent results were obtained in model cells. These findings indicate that GM3 acts with nephrin in a collaborative manner in the cell membrane. Taken together, elevated levels of GM3 stabilize nephrin, which is a key molecule of the slit diaphragm, by enhancing the environment of the cell membrane and preventing albuminuria. This study provides novel insight into new drug discovery, which may offer a new therapy for kidney disease with albuminuria.

DOI： 10.1038/s41598-022-20265-w

Web of Science

Scopus

記述言語：日本語   出版者・発行元：Biochimica et Biophysica Acta - General Subjects  

Swainsonine (SWA), a potent inhibitor of class II α-mannosidases, is present in a number of plant species worldwide and causes severe toxicosis in livestock grazing these plants. The mechanisms underlying SWA-induced animal poisoning are not fully understood. In this study, we analyzed the alterations that occur in N- and free N-glycomic upon addition of SWA to HepG2 cells to understand better SWA-induced glycomic alterations. After SWA addition, we observed the appearance of SWA-specific glycomic alterations, such as unique fucosylated hybrid-type and fucosylated M5 (M5F) N-glycans, and a remarkable increase in all classes of Gn1 FNGs. Further analysis of the context of these glycomic alterations showed that (fucosylated) hybrid type N-glycans were not the precursors of these Gn1 FNGs and vice versa. Time course analysis revealed the dynamic nature of glycomic alterations upon exposure of SWA and suggested that accumulation of free N-glycans occurred earlier than that of hybrid-type N-glycans. Hybrid-type N-glycans, of which most were uniquely core fucosylated, tended to increase slowly over time, as was observed for M5F N-glycans. Inhibition of swainsonine-induced unique fucosylation of hybrid N-glycans and M5 by coaddition of 2-fluorofucose caused significant increases in paucimannose- and fucosylated paucimannose-type N-glycans, as well as paucimannose-type free N-glycans. The results not only revealed the gross glycomic alterations in HepG2 cells induced by swainsonine, but also provide information on the global interrelationships between glycomic alterations.

DOI： 10.1016/j.bbagen.2022.130168

Web of Science

Scopus

担当区分：責任著者   記述言語：英語   掲載種別：論文集(書籍)内論文  

DOI： DOI: 10.1007/978-1-0716-2281-0_13

J-GLOBAL