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更新于：2025-05-07

MIOS

更新于：2025-05-07

基本信息

别名

FLJ20323、GATOR complex protein MIOS、meiosis regulator for oocyte development

+ [5]

简介

As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:23723238, PubMed:26586190, PubMed:27487210, PubMed:35831510, PubMed:36528027). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:26586190, PubMed:27487210, PubMed:35831510, PubMed:36528027). GATOR2 probably acts as an E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:25263562, PubMed:25457612, PubMed:26586190, PubMed:27487210). Within the GATOR2 complex, MIOS is required to prevent autoubiquitination of WDR24, the catalytic subunit of the complex (PubMed:35831510). The GATOR2 complex is required for brain myelination (By similarity).

关联

项与 MIOS 相关的药物

Tanshinone IIA

靶点

CES x MIOS

作用机制

CES 抑制剂 [+1]

在研机构

Royal Holloway University of London [+2]

原研机构

財團法人彰化基督教醫院

在研适应症

胶质母细胞瘤 [+3]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 MIOS 相关的临床试验

ChiCTR2400093487

/ Recruiting早期临床1期IIT

Clinical efficacy and safety evaluation of dissolving acupoint microneedles with tanshinone IIA in the treatment of chronic stable angina

开始日期2024-06-06

申办/合作机构-

ChiCTR1800017926

/ SuspendedN/AIIT

Safety and efficacy of topical Tanshinone gel treatment of infantile hemangioma: a prospective, multicenter, self-controlled clinical trial.

开始日期2018-09-01

申办/合作机构-

ChiCTR-TQR-14005142

/ RecruitingN/AIIT

Therapeutic effects of tanshinone IIA towards early renal damage in patients with type 2 diabetes

开始日期2014-09-01

申办/合作机构-

100 项与 MIOS 相关的临床结果

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100 项与 MIOS 相关的转化医学

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0 项与 MIOS 相关的专利（医药）

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项与 MIOS 相关的文献（医药）

2024-03-29·Bioscience Reports

New insights into GATOR2-dependent interactions and its conformational changes in amino acid sensing

Article

作者: Wu, Geng ; Sun, Xuan ; Yang, Can

AbstractEukaryotic cells coordinate growth under different environmental conditions via mechanistic target of rapamycin complex 1 (mTORC1). In the amino-acid-sensing signalling pathway, the GATOR2 complex, containing five evolutionarily conserved subunits (WDR59, Mios, WDR24, Seh1L and Sec13), is required to regulate mTORC1 activity by interacting with upstream CASTOR1 (arginine sensor) and Sestrin2 (leucine sensor and downstream GATOR1 complex). GATOR2 complex utilizes β-propellers to engage with CASTOR1, Sestrin2 and GATOR1, removal of these β-propellers results in substantial loss of mTORC1 capacity. However, structural information regarding the interface between amino acid sensors and GATOR2 remains elusive. With the recent progress of the AI-based tool AlphaFold2 (AF2) for protein structure prediction, structural models were predicted for Sentrin2-WDR24-Seh1L and CASTOR1-Mios β-propeller. Furthermore, the effectiveness of relevant residues within the interface was examined using biochemical experiments combined with molecular dynamics (MD) simulations. Notably, fluorescence resonance energy transfer (FRET) analysis detected the structural transition of GATOR2 in response to amino acid signals, and the deletion of Mios β-propeller severely impeded that change at distinct arginine levels. These findings provide structural perspectives on the association between GATOR2 and amino acid sensors and can facilitate future research on structure determination and function.

2023-01-01·Molecular Cell

Ring domains are essential for GATOR2-dependent mTORC1 activation

Article

作者: Liu, Songlei ; Dai, Xiaoming ; Inuzuka, Hiroyuki ; Zhang, Tao ; Zhou, Hongfei ; Xiao, Jianru ; Wang, Ping ; Jiang, Cong ; Fu, Tianmin ; He, Shaohui ; Guo, Jianping ; Li, Dali ; Yu, Haihong ; Fang, Lan ; Wei, Wenyi ; Pan, Weijuan

The GATOR2-GATOR1 signaling axis is essential for amino-acid-dependent mTORC1 activation. However, the molecular function of the GATOR2 complex remains unknown. Here, we report that disruption of the Ring domains of Mios, WDR24, or WDR59 completely impedes amino-acid-mediated mTORC1 activation. Mechanistically, via interacting with Ring domains of WDR59 and WDR24, the Ring domain of Mios acts as a hub to maintain GATOR2 integrity, disruption of which leads to self-ubiquitination of WDR24. Physiologically, leucine stimulation dissociates Sestrin2 from the Ring domain of WDR24 and confers its availability to UBE2D3 and subsequent ubiquitination of NPRL2, contributing to GATOR2-mediated GATOR1 inactivation. As such, WDR24 ablation or Ring deletion prevents mTORC1 activation, leading to severe growth defects and embryonic lethality at E10.5 in mice. Hence, our findings demonstrate that Ring domains are essential for GATOR2 to transmit amino acid availability to mTORC1 and further reveal the essentiality of nutrient sensing during embryonic development.

2022-10-01·Microbiological Research

Genetic mapping of a bioethanol yeast strain reveals new targets for hydroxymethylfurfural- and thermotolerance

Article

作者: Maneira, Carla ; de Mello, Fellipe da Silveira Bezerra ; Teixeira, Gleidson Silva ; Coradini, Alessandro Luis Venega ; Pereira, Gonçalo Amarante Guimarães ; Furlan, Monique ; Carazzolle, Marcelo Falsarella

Current technology that enables bioethanol production from agricultural biomass imposes harsh conditions for Saccharomyces cerevisiae's metabolism. In this work, the genetic architecture of industrial bioethanol yeast strain SA-1 was evaluated. SA-1 segregant FMY097 was previously described as highly aldehyde resistant and here also as thermotolerant: two important traits for the second-generation industry. A Quantitative Trait Loci (QTL) mapping of 5-hydroxymethylfurfural (HMF) -resistant segregants of hybrid FMY097/BY4742 disclosed a region in chromosome II bearing alleles with uncommon non-synonymous (NS) single nucleotide polymorphisms (SNPs) in FMY097: MIX23, PKC1, SEA4, and SRO77. Allele swap to susceptible laboratory strain BY4742 revealed that SEA4^FMY097 enhances robustness towards HMF, but the industrial fitness could not be fully recovered. The genetic network arising from the causative genes in the QTL window suggests that intracellular signaling TOR (Target of Rapamycin) and CWI (Cell Wall Integrity) pathways are regulators of this phenotype in FMY097. Because the QTL mapping did not result in one major allelic contribution to the evaluated trait, a background effect in FMY097's HMF resistance is expected. Quantification of NADPH - cofactor implied in endogenous aldehyde detoxification reactions - supports the former hypothesis, given its high availability in FMY097. Regarding thermotolerance, SEA4^FMY097 grants BY4742 ability to grow in temperatures as high as 38 ºC in liquid, while allele PKC1^FMY097 allows growth up to 40 ºC in solid medium. Both SEA4^FMY097 and PKC1^FMY097 encode rare NS SNPs, not found in other > 1013S. cerevisiae. Altogether, these findings point towards crucial membrane and stress mediators for yeast robustness.

项与 MIOS 相关的新闻（医药）

2024-12-16

·Cytiva学堂

干细胞的收获与制剂高回收率革新解决方案

在当今医疗科技飞速发展的时代，干细胞疗法作为再生医学的璀璨明珠，正逐步展现其巨大的治疗潜力。干细胞，因其具有自我更新和分化为多种细胞类型的能力，被视为治疗多种疾病的新希望，特别是在组织修复、疾病模型建立以及药物筛选等领域展现出广泛的应用前景。据CDE官网显示，截至目前，共有101款干细胞药物获准默许进入临床试验。图1：CDE官网随着市场对同种异体细胞与基因疗法的投资不断增加，干细胞的规模化扩增已成为研究热点。然而，干细胞培养的复杂性和对加工过程的高要求，使得干细胞疗法的商业化面临诸多挑战。如何在保证细胞活性、回收率和多能性的同时，实现低体积的终端产品，成为干细胞加工领域亟待解决的问题。 Cytiva干细胞产品解决方案在此背景下，Cytiva凭借其先进的Sepax C-Pro细胞处理系统，为干细胞的收获与配制提供了创新解决方案。该系统不仅能够自动化工作流程，还能确保关键细胞属性，如高活性、高回收率和多能性得以维持。 Sepax C-Pro系统不仅能够自动化工作流程，减少人工操作带来的误差；还通过其自动化的CultureWash软件，实现了对骨髓间充质干细胞 (MSCs) 和诱导多能干细胞 (iPSCs) 的高效处理；研究人员利用该系统，成功创建了两个新型参数集，分别用于处理这两种干细胞，实现了超过82%的回收率，同时保持了细胞的高存活率和多能性。图2：Cytiva细胞处理系统，Sepax C Pro（左）Sefia S2000（右） MSC 使用CultureWash C-Pro参数设置如表1所示，三次重复运行（运行1-3次），输入1×107个活细胞，平均回收率为90.0%。处理后的活力仍然很高 (>98%) ，与预处理前的活力（97%至98%）相当。通过CD73、CD90和CD105的共表达，最终产物的干性测量大于98%。为了确定更大的细胞数量输入是否会影响恢复和活力，我们进行了一次运行（运行4），输入1.5×107个活细胞。结果表明，回收率为99.3%，后处理活力为98.5%，表明增加输入细胞数不降低回收率。图3：每次运行的总活细胞回收率，平均90%。(B) 每次运行前后culturewash细胞活力的比较。(C) 流式细胞术门控显示多能性标记CD73、CD90和CD105 iPSC 第一次测试回收率偏低（低于80%），通过调整回收模式，依据细胞的特定直径调整IV等参数，在之后的测试中均达到较高的回收率，测试中最高达85.1%。且在处理前后，细胞的活率显示有所增加，可能是由于Sepax的离心步骤有助于去除死细胞。此外，为了确认处理是否影响iPSC的多能性，用流式细胞术定量测定胚胎干细胞标志物SOX2和OCT3/4的表达。结果显示＞87%的SEA4 / OCT3_4 / SOX2染色，表明该过程没有改变iPSC的多能性。图4：(A) 每次运行总活细胞回收率 (B) CultureWash处理前后细胞活率对比 (C) 流式细胞分析多能性标志OCT3/4、SSEA4和SOX2 结论经过一系列的验证与测试，Cytiva细胞处理系统在干细胞处理中表现出优越性能。结果显示，无论是MSCs还是iPSCs，其存活率、回收率和多能性均得到了有效保持，且能够去除死细胞。这一成果不仅为干细胞疗法的临床应用提供了自动、密闭、高效的有力支持，也为干细胞研究的深入发展奠定了坚实基础。欢迎扫码了解更多关于Xuri干细胞培养相关应用

细胞疗法基因疗法临床研究