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The scaffold protein IQGAP1 promotes reorientation of epithelial cell polarity at the two-cell stage for cystogenesis 支架蛋白 IQGAP1 可促进上皮细胞极性在双细胞阶段的重新定向,从而促进囊肿生成。
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-10-08 DOI: 10.1111/gtc.13169
Michihiro Horikawa, Junya Hayase, Sachiko Kamakura, Akira Kohda, Masafumi Nakamura, Hideki Sumimoto

A single epithelial cell embedded in extracellular matrix (ECM) can proliferate to form an apical lumen-harboring cyst, whose formation is a fundamental step in epithelial organ development. At an early two-cell stage after cell division, the cell doublet typically displays “inverted” polarity, with apical and basolateral proteins being located to the ECM-facing and cell–cell-contacting plasma membranes, respectively. Correct cystogenesis requires polarity reorientation, a process containing apical protein endocytosis from the ECM-abutting periphery and subsequent apical vesicle delivery to a cell–cell contact site for lumen formation. Here, we show that downstream of the ECM-signal-transducer β1-integrin, Rac1, and its effector IQGAP1 promote apical protein endocytosis, contributing to polarity reorientation of mammalian epithelial Madin-Darby canine kidney (MDCK) cells at a later two-cell stage in three-dimensional culture. Rac1–GTP facilitates IQGAP1 interaction with the Rac-specific activator Tiam1, which also contributes to the endocytosis and enhances the effect of IQGAP1. These findings suggest that Tiam1 and IQGAP1 form a positive feedback loop to activate Rac1. With Rac1–GTP, IQGAP1 also binds to AP2α, an adaptor protein subunit for clathrin-mediated endocytosis; depletion of the AP2 complex impairs apical protein endocytosis in MDCK doublets. Thus, Rac1 likely participates in polarity reorientation at the two-cell stage via its interaction with IQGAP1.

嵌入细胞外基质(ECM)的单个上皮细胞可增殖形成一个顶端有腔的囊肿,其形成是上皮器官发育的基本步骤。在细胞分裂后的早期双细胞阶段,细胞双层通常呈现 "倒置 "极性,顶端蛋白和基底蛋白分别位于面向 ECM 的质膜和与细胞接触的质膜上。正确的囊肿形成需要极性重新定向,这一过程包括顶端蛋白从与 ECM 相接的外围内吞,以及随后顶端囊泡被输送到细胞-细胞接触点以形成管腔。在这里,我们发现在 ECM 信号转导因子 β1-integrin 的下游,Rac1 及其效应物 IQGAP1 促进了顶端蛋白的内吞,有助于哺乳动物上皮 Madin-Darby 犬肾(MDCK)细胞在三维培养的后期两细胞阶段的极性重新定向。Rac1-GTP促进了IQGAP1与Rac特异性激活剂Tiam1的相互作用,Tiam1也有助于内吞并增强了IQGAP1的作用。这些发现表明,Tiam1 和 IQGAP1 形成了激活 Rac1 的正反馈回路。通过 Rac1-GTP,IQGAP1 还能与 AP2α 结合,AP2α 是一种用于凝集素介导的内吞的适配蛋白亚基;AP2 复合物的耗竭会影响 MDCK 双倍体的顶端蛋白内吞。因此,Rac1 很可能通过与 IQGAP1 的相互作用参与了双细胞阶段的极性重新定向。
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引用次数: 0
Evolution of the Cdk4/6–Cdkn2 system in invertebrates 无脊椎动物中 Cdk4/6-Cdkn2 系统的进化。
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-10-08 DOI: 10.1111/gtc.13165
Shiori Yuki, Shunsuke Sasaki, Yuta Yamamoto, Fumika Murakami, Kazumi Sakata, Isato Araki

The cell cycle is driven by cyclin-dependent kinases (Cdks). The decision whether the cell cycle proceeds is made during G1 phase, when Cdk4/6 functions. Cyclin-dependent kinase inhibitor 2 (Cdkn2) is a specific inhibitor of Cdk4/6, and their interaction depends on D84 in Cdkn2 and R24/31 in Cdk4/6. This knowledge is based mainly on studies in mammalian cells. Here, we comprehensively analyzed Cdk4/6 and Cdkn2 in invertebrates and found that Cdk4/6 was present in most of the investigated phyla, but the distribution of Cdkn2 was rather uneven among and within the phyla. The positive charge of R24/R31 in Cdk4/6 was conserved in all analyzed species in phyla with Cdkn2. The presence of Cdkn2 and the conservation of the positive charge were statistically correlated. We also found that Cdkn2 has been tightly linked to Fas associated factor 1 (Faf1) during evolution. We discuss potential interactions between Cdkn2 and Cdk4/6 in evolution and the possible cause of the strong conservation of the microsynteny.

细胞周期由细胞周期蛋白依赖性激酶(Cdks)驱动。细胞周期是否继续是在 G1 期决定的,此时 Cdk4/6 发挥作用。细胞周期蛋白依赖性激酶抑制剂 2(Cdkn2)是 Cdk4/6 的特异性抑制剂,它们之间的相互作用取决于 Cdkn2 中的 D84 和 Cdk4/6 中的 R24/31。这些知识主要基于对哺乳动物细胞的研究。在这里,我们对无脊椎动物中的 Cdk4/6 和 Cdkn2 进行了全面分析,发现 Cdk4/6 存在于大多数被研究的门类中,但 Cdkn2 在门类之间和门类内部的分布相当不均匀。Cdk4/6中R24/R31的正电荷在有Cdkn2的所有分析物种中都是一致的。Cdkn2 的存在与正电荷的保留在统计学上有相关性。我们还发现,在进化过程中,Cdkn2 与 Fas 相关因子 1(Faf1)紧密相连。我们讨论了 Cdkn2 和 Cdk4/6 在进化过程中可能发生的相互作用,以及微合成关系保持不变的可能原因。
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引用次数: 0
Roles of ZEB1 and ZEB2 in E-cadherin expression and cell aggressiveness in head and neck cancer ZEB1和ZEB2在头颈癌E-粘连蛋白表达和细胞侵袭性中的作用
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-10-03 DOI: 10.1111/gtc.13167
Arisa Kinouchi, Takahiro Jubashi, Rikito Tatsuno, Jiro Ichikawa, Kaname Sakamoto, Daiju Sakurai, Tomonori Kawasaki, Hiroki Ishii, Keiji Miyazawa, Masao Saitoh

Zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in cancer cell differentiation and metastasis, and has been well studied in the field of cancer cell biology. ZEB2 has a highly similar conformation to ZEB1, but its role in head and neck squamous cell carcinoma (HNSCC) cells is not fully understood. Here, we separately overexpressed ZEB1 and ZEB2 in C57BL/6 mouse oral cancer (MOC) cells and investigated their cellular characteristics, including E-cadherin levels, motile properties, chemoresistance, and metastatic ability in immunocompetent mice. Both ZEB1 and ZEB2 overexpression reduced epithelial traits and converted cells to an aggressive phenotype. Surprisingly, ZEB1 overexpression increased the endogenous level of ZEB2 in MOC cells, and vice versa. The molecular mechanisms underlying these findings remain unclear. However, the in vitro anchorage-independent growth of MOC cells overexpressing ZEB2 was considerably greater than that of MOC cells overexpressing ZEB1. These findings suggest that ZEB2, like ZEB1, has the ability to induce the differentiation of cancer cells into those with highly aggressive traits.

锌指E盒结合同源染色体1(ZEB1)已被确定为癌细胞分化和转移的关键因素,并在癌细胞生物学领域得到了深入研究。ZEB2与ZEB1具有高度相似的构象,但其在头颈部鳞状细胞癌(HNSCC)细胞中的作用还不完全清楚。在这里,我们在 C57BL/6 小鼠口腔癌(MOC)细胞中分别过表达了 ZEB1 和 ZEB2,并研究了它们的细胞特性,包括 E-粘连蛋白水平、运动特性、化疗抗性以及在免疫功能正常小鼠体内的转移能力。ZEB1和ZEB2的过表达都降低了上皮性状,并使细胞转变为侵袭性表型。令人惊讶的是,ZEB1的过表达增加了MOC细胞中ZEB2的内源性水平,反之亦然。这些发现的分子机制尚不清楚。然而,过表达 ZEB2 的 MOC 细胞的体外锚定依赖性生长大大高于过表达 ZEB1 的 MOC 细胞。这些发现表明,ZEB2 与 ZEB1 一样,能够诱导癌细胞分化为具有高度侵袭性的细胞。
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引用次数: 0
Regular exercise suppresses steatosis-associated liver cancer development by degrading E2F1 and c-Myc via circadian gene upregulation 通过昼夜节律基因上调降解E2F1和c-Myc,定期运动可抑制脂肪变性相关肝癌的发展。
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-10-02 DOI: 10.1111/gtc.13161
Vu Thuong Huyen, Kanae Echizen, Ryota Yamagishi, Miho Kumagai, Yoshiki Nonaka, Takahiro Kodama, Tatsuya Ando, Megumu Yano, Naoki Takada, Masaki Takasugi, Fumitaka Kamachi, Naoko Ohtani

Regular exercise is believed to suppress cancer progression. However, the precise molecular mechanisms by which exercise prevents cancer development remain unclear. In this study, using a steatosis-associated liver cancer mouse model, we found that regular exercise at a speed of 18 m/min for 20 min daily suppressed liver cancer development. To explore the underlying mechanisms, we examined the gene expression profiles in the livers of the exercise and non-exercise groups. The expressions of circadian genes, such as Per1 and Cry2, were upregulated in the exercise group. As circadian rhythm disruption is known to cause various diseases, including cancer, improving circadian rhythm through exercise could contribute to cancer prevention. We further found that the expression of a series of E2F1 and c-Myc target genes that directly affect the proliferation of cancer cells was downregulated in the exercise group. However, the expression of E2F1 and c-Myc was transcriptionally unchanged but degraded at the post-translational level by exercise. Cry2, which is regulated by the Skp1-Cul1-FBXL3 (SCFFBXL3) ubiquitin ligase complex by binding to FBXL3, can form a complex with E2F1 and c-Myc, which we think is the mechanism to degrade them. Our study revealed a previously unknown mechanism by which exercise prevents cancer development.

经常锻炼被认为可以抑制癌症的发展。然而,运动预防癌症发展的确切分子机制仍不清楚。在这项研究中,我们利用脂肪变性相关肝癌小鼠模型发现,每天以 18 米/分钟的速度进行 20 分钟的有规律运动能抑制肝癌的发展。为了探索其潜在机制,我们研究了运动组和非运动组肝脏中的基因表达谱。在运动组中,Per1 和 Cry2 等昼夜节律基因的表达上调。众所周知,昼夜节律紊乱会导致包括癌症在内的多种疾病,因此通过运动改善昼夜节律有助于预防癌症。我们进一步发现,运动组中一系列直接影响癌细胞增殖的 E2F1 和 c-Myc 靶基因的表达下调。然而,E2F1和c-Myc的表达在转录水平上没有变化,但在翻译后水平上却因运动而降解。Cry2受Skp1-Cul1-FBXL3(SCFFBXL3)泛素连接酶复合物的调控,通过与FBXL3结合,可与E2F1和c-Myc形成复合物,我们认为这就是降解它们的机制。我们的研究揭示了运动预防癌症发展的一种未知机制。
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引用次数: 0
Search for putative gene regulatory motifs in CAHS3, linked to anhydrobiosis in a tardigrade Ramazzottius varieornatus, in vivo and in silico 寻找 CAHS3 中的推定基因调控基团,在体内和硅学中研究与迟行龙 Ramazzottius varieornatus 的无水生物症有关的基因调控基团。
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-09-30 DOI: 10.1111/gtc.13168
Sora Ishikawa, Sae Tanaka, Kazuharu Arakawa

Tardigrades possess the ability to enter an almost completely dehydrated state, anhydrobiosis. The CAHS (cytosolic abundant heat-soluble) protein family has been identified as one of the anhydrobiosis-related proteins. In particular, CAHS3 protein from an anhydrobiotic tardigrade, Ramazzottius varieornatus, shows heat-solubility and reversible condensation and is one of the most highly expressed among the CAHS paralogs. A recently developed tardigrade-specific vector showed tissue-specific expression of RvCAHS3 most pronounced in the epidermis in vivo, contrary to the idea that anhydrobiotic genes are uniformly expressed in all tardigrade cells. In this study, we investigated the regulation of RvCAHS3 gene expression through in vivo expression experiments using tardigrade vectors with a series of truncated upstream regions coupled with in silico analysis to identify the anhydrobiosis-related genes that are expressed under the same regulatory system as RvCAHS3. As a result, the 300–350 bp region upstream of RvCAHS3 is critical for regulating gene expression in tardigrade vector experiments, and three motifs conserved between two species of anhydrobiotic tardigrades were identified within a 500 bp region directly upstream of RvCAHS3 start codon. These motifs, which have also been identified upstream of other CAHS genes, could be associated with the regulatory system of anhydrobiosis-related genes in tardigrades.

迟发型生物具有进入几乎完全脱水状态(无水生生物)的能力。CAHS(细胞膜丰富热溶性)蛋白家族已被确认为与无水生物状态相关的蛋白之一。特别是,来自一种水生沙蜥(Ramazzottius varieornatus)的 CAHS3 蛋白具有热溶解性和可逆缩合性,是 CAHS 旁系亲属中表达量最高的蛋白之一。最近开发的一种游仆虫特异性载体显示,RvCAHS3的组织特异性表达在体内表皮中最为明显,这与无水生生物基因在所有游仆虫细胞中均匀表达的观点相反。在本研究中,我们通过使用带有一系列截短上游区域的沙蜥载体进行体内表达实验,并结合硅学分析,研究了 RvCAHS3 基因的表达调控,以确定与 RvCAHS3 在相同调控系统下表达的抗水解相关基因。结果发现,RvCAHS3 上游的 300-350 bp 区域对于调控沙蜥载体实验中的基因表达至关重要,并且在 RvCAHS3 起始密码子正上方的 500 bp 区域内发现了两个无水生生物沙蜥物种之间的三个保守基团。在其他 CAHS 基因的上游也发现了这些基团,它们可能与沙蜥无水生生物相关基因的调控系统有关。
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引用次数: 0
Meta-analysis of gonadal transcriptome provides novel insights into sex change mechanism across protogynous fishes 性腺转录组的元分析为了解原雌性鱼类的性别变化机制提供了新的视角。
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-09-29 DOI: 10.1111/gtc.13166
Ryo Nozu, Mitsutaka Kadota, Masaru Nakamura, Shigehiro Kuraku, Hidemasa Bono

Protogyny, being capable of changing from female to male during their lifetime, is prevalent in 20 families of teleosts but is believed to have evolved within specific evolutionary lineages. Therefore, shared regulatory factors governing the sex change process are expected to be conserved across protogynous fishes. However, a comprehensive understanding of this mechanism remains elusive. To identify these factors, we conducted a meta-analysis using gonadal transcriptome data from seven species. We curated data pairs of ovarian tissue and transitional gonad, and employed ratios of expression level as a unified criterion for differential expression, enabling a meta-analysis across species. Our approach revealed that classical sex change-related genes exhibited differential expression levels between the ovary and transitional gonads, consistent with previous reports. These results validate our methodology's robustness. Additionally, we identified novel genes not previously linked to gonadal sex change in fish. Notably, changes in the expression levels of acetoacetyl-CoA synthetase and apolipoprotein Eb, which are involved in cholesterol synthesis and transport, respectively, suggest that the levels of cholesterol, a precursor of steroid hormones crucial for sex change, are decreased upon sex change onset in the gonads. This implies a potential universal influence of cholesterol dynamics on gonadal transformation in protogyny.

原雌性鱼类在其一生中能够从雌性变为雄性,这种现象在 20 个远洋鱼类科中普遍存在,但据信是在特定的进化系中进化而来的。因此,在原雌性鱼类中,管理变性过程的共同调控因子预计是保守的。然而,对这一机制的全面了解仍然遥遥无期。为了确定这些因素,我们利用七个物种的性腺转录组数据进行了一项荟萃分析。我们整理了卵巢组织和过渡性性腺的数据对,并采用表达水平比作为差异表达的统一标准,从而实现了跨物种的荟萃分析。我们的方法发现,经典的性变化相关基因在卵巢和过渡性性腺之间表现出不同的表达水平,这与之前的报道一致。这些结果验证了我们方法的稳健性。此外,我们还发现了以前与鱼类性腺性别变化无关的新基因。值得注意的是,分别参与胆固醇合成和转运的乙酰乙酰-CoA合成酶和脂蛋白Eb的表达水平发生了变化,这表明性腺发生性变化时,胆固醇--一种对性变态至关重要的类固醇激素的前体--的水平降低了。这意味着胆固醇的动态变化对原生动物性腺的转变具有潜在的普遍影响。
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引用次数: 0
The repertoire of G-protein-coupled receptor variations in the Japanese population 54KJPN 日本人口中 G 蛋白偶联受体变异的剧目 54KJPN.
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-09-23 DOI: 10.1111/gtc.13164
Tatsuya Ikuta, Riko Suzuki, Asuka Inoue

G-protein-coupled receptors (GPCRs) are the largest superfamily in the human genome and the major targets for the market drugs. Recent massive genomics studies revealed numerous natural variations in the general population. 54KJPN is the most extensive Japanese population genomics study, curating the whole genome sequences from about 54,000 individuals. Here, by analyzing 390 non-olfactory GPCR genes in the 54KJPN dataset, we annotated 25,443 missense single-nucleotide variations. Among them, we found 120 major variations that appear with an allele frequency greater than 0.5, including variations that occurred on posttranslational modification sites. Structural alignment of GPCRs using the generic numbering system in the GPCRdb reveals enrichment of alterations in the conserved arginine residue within the DRY motif, which contributes to downstream G-protein signaling. A comparison with the worldwide 1000 Genomes Project (1KGP) dataset found 23 variations that were present exclusively in the 54KJPN dataset. This study will be the basis for future pharmacogenomics studies for the Japanese population.

G 蛋白偶联受体(GPCR)是人类基因组中最大的超家族,也是市场上药物的主要靶点。最近的大规模基因组研究揭示了普通人群中的大量自然变异。54KJPN 是最广泛的日本人群基因组学研究,收集了约 54,000 人的全基因组序列。在这里,通过分析 54KJPN 数据集中的 390 个非嗅觉 GPCR 基因,我们注释了 25,443 个错义单核苷酸变异。其中,我们发现了等位基因频率大于 0.5 的 120 个主要变异,包括发生在翻译后修饰位点上的变异。使用 GPCRdb 中的通用编号系统对 GPCR 进行结构比对,发现 DRY 矩阵中保守的精氨酸残基发生了富集变异,而这有助于下游的 G 蛋白信号转导。与全球千人基因组计划(1KGP)数据集的比较发现,有 23 个变异只存在于 54KJPN 数据集中。这项研究将成为未来日本人口药物基因组学研究的基础。
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引用次数: 0
Elimination of physiological senescent cutaneous cells in a novel p16-dependent senolytic mouse model impacts lipid metabolism in skin aging 在新型 p16 依赖性衰老小鼠模型中消除生理性衰老皮肤细胞会影响皮肤老化过程中的脂质代谢
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-09-16 DOI: 10.1111/gtc.13163
Yuma Sugiyama, Yoichiro Kawabe, Tanenobu Harada, Yu Aoki, Keiko Tsuji, Daijiro Sugiyama, Mitsuo Maruyama

The evidence of the correlation between cellular senescence and aging has increased in research with animal models. These models have been intentionally generated to target and regulate cellular senescent cells with the promoter activity of p16Ink4a or p19Arf, genes that are highly expressed in aging cells. However, the senolytic efficiency in various organs and cells from these models represents unexpected variation and diversity in some cases. We have generated a novel knock-in model, p16tdT-hDTR mice, which possess tdTomato and human diphtheria toxin receptor (hDTR) downstream of Cdkn2a, an endogenous p16Ink4a gene. We successfully demonstrated that p16-derived tdTomato and hDTR expressions are observed in these mouse embryo fibroblasts and following treatment with diphtheria toxin (DT) eliminates those cells. Furthermore, we demonstrated the efficacy of eliminating p16-positive cells in vivo, and also observed a tendency to decrease their cutaneous SA-β-gal activity after subcutaneous DT injection into p16tdT-hDTR mice. In particular, comprehensive gene expression analysis in skin revealed that upregulated genes related to lipid metabolisms with aging exhibited remarkable expressions under the senolysis. These results clearly unveiled p16-positive senescent cells contribute to age-related changes in skin.

在动物模型研究中,细胞衰老与衰老之间相关性的证据越来越多。这些动物模型是有意识地利用衰老细胞中高表达基因 p16Ink4a 或 p19Arf 的启动子活性来靶向和调控细胞衰老。然而,这些模型在不同器官和细胞中的衰老效率在某些情况下存在意想不到的差异和多样性。我们生成了一种新的基因敲入模型--p16tdT-hDTR小鼠,它在内源性p16Ink4a基因Cdkn2a的下游具有tdTomato和人白喉毒素受体(hDTR)。我们成功地证明,在这些小鼠胚胎成纤维细胞中观察到了 p16 衍生的 tdTomato 和 hDTR 表达,并在用白喉毒素(DT)处理后消除了这些细胞。此外,我们还证明了在体内消除 p16 阳性细胞的功效,并观察到 p16tdT-hDTR 小鼠皮下注射 DT 后,其皮肤 SA-β-gal 活性呈下降趋势。特别是,皮肤中的综合基因表达分析表明,与脂质代谢相关的基因随衰老而上调,在衰老过程中表现出显著的表达。这些结果清楚地揭示了 p16 阳性衰老细胞导致了皮肤与年龄相关的变化。
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引用次数: 0
Accelerated BDNF expression in visceral white adipose tissues following high-fat diet feeding in mice 小鼠摄入高脂饮食后,内脏白色脂肪组织中 BDNF 的表达加速。
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-09-15 DOI: 10.1111/gtc.13162
Kurumi Sakata, Mamoru Fukuchi

Brain-derived neurotrophic factor (BDNF) is expressed in the white adipose tissues (WATs), and the expression increases during high-fat diet (HFD) feeding, implicating its role in obesity. Here, we focused on BDNF expression in epididymal WAT (eWAT), a visceral adipose tissue, in mice. During 2 weeks of HFD feeding, Bdnf mRNA expression in eWAT slightly increased, but a robust increase was observed after 8 weeks of HFD feeding. This upregulation of Bdnf mRNA was correlated with significant induction of hypoxia-inducible factor 1α (Hif1α) and platelet-derived growth factor subunit B (Pdgfb) mRNA in eWAT following 8 weeks of HFD feeding. Furthermore, the increased expression of the M1 macrophage markers was strongly correlated with the elevation of Bdnf mRNA in the eWAT. Notably, 8 weeks of HFD feeding significantly elevated Tnfα mRNA expression in eWAT, while no such induction was observed in inguinal WAT (iWAT). In contrast, the expression of Adipoq (adiponectin), implicated in improved insulin sensitivity and anti-inflammatory effects, was significantly upregulated in iWAT, but not in eWAT. Thus, our study may show the role of BDNF in eWAT in obesity models, potentially contributing to the pathological state of visceral adipose tissues.

脑源性神经营养因子(BDNF)在白色脂肪组织(WATs)中表达,并且在高脂饮食(HFD)喂养期间表达增加,这表明它在肥胖中的作用。在这里,我们重点研究了BDNF在小鼠附睾WAT(eWAT)(一种内脏脂肪组织)中的表达。在喂食高氟日粮 2 周期间,eWAT 中的 Bdnf mRNA 表达量略有增加,但在喂食高氟日粮 8 周后,观察到了显著的增加。Bdnf mRNA的上调与低氧诱导因子1α(Hif1α)和血小板衍生生长因子亚基B(Pdgfb)mRNA在喂食HFD 8周后的eWAT中的显著诱导相关。此外,M1 巨噬细胞标记物表达的增加与 eWAT 中 Bdnf mRNA 的升高密切相关。值得注意的是,8周高密度脂蛋白喂养显著提高了eWAT中Tnfα mRNA的表达,而在腹股沟WAT(iWAT)中没有观察到这种诱导。相反,与改善胰岛素敏感性和抗炎作用有关的 Adipoq(脂肪连通素)的表达在 iWAT 中明显上调,而在 eWAT 中则没有。因此,我们的研究可能显示了肥胖模型中 BDNF 在 eWAT 中的作用,这可能会导致内脏脂肪组织的病理状态。
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引用次数: 0
Neonatal Fc receptor is a functional receptor for classical human astrovirus 新生儿 Fc 受体是经典人类星状病毒的功能性受体
IF 1.3 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-09-12 DOI: 10.1111/gtc.13160
Kei Haga, Takashi Tokui, Kana Miyamoto, Reiko Takai-Todaka, Shiori Kudo, Azusa Ishikawa, Ryoka Ishiyama, Akiko Kato, Masaru Yokoyama, Kazuhiko Katayama, Akira Nakanishi

Human astrovirus (HAstV) is a global cause of gastroenteritis in infants, the elderly, and the immunocompromised. However, the molecular mechanisms that control its susceptibility are not fully understood, as the functional receptor used by the virus has yet to be identified. Here, a genome-wide CRISPR-Cas9 library screen in Caco2 cells revealed that the neonatal Fc receptor (FcRn) can function as a receptor for classical HAstV (Mamastrovirus genotype 1). Deletion of FCGRT or B2M, which encode subunits of FcRn, rendered Caco2 cells and intestinal organoid cells resistant to HAstV infection. We also showed that human FcRn expression renders non-susceptible cells permissive to viral infection and that FcRn binds directly to the HAstV spike protein. Therefore, our findings provide insight into the entry mechanism of HAstV into susceptible cells. We anticipate that this information can be used to develop new therapies targeting human astroviruses, providing new strategies to treat this global health issue.

人类星状病毒(HAstV)是导致婴儿、老年人和免疫力低下者患肠胃炎的全球性病因。然而,由于病毒使用的功能受体尚未确定,控制其易感性的分子机制尚未完全明了。本文在 Caco2 细胞中进行的全基因组 CRISPR-Cas9 文库筛选发现,新生儿 Fc 受体(FcRn)可作为经典 HAstV(Mamastrovirus 基因型 1)的受体。缺失编码 FcRn 亚基的 FCGRT 或 B2M 会使 Caco2 细胞和肠道类细胞对 HAstV 感染产生抗性。我们的研究还表明,人类 FcRn 的表达可使非易感细胞允许病毒感染,而且 FcRn 可直接与 HAstV 的尖峰蛋白结合。因此,我们的研究结果让我们深入了解了 HAstV 进入易感细胞的机制。我们预计这些信息可用于开发针对人类星状病毒的新疗法,为治疗这一全球性健康问题提供新策略。
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引用次数: 0
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