更新于：2024-05-01

SPAG9

sperm associated antigen 9

更新于：2024-05-01

基本信息

别名

C-Jun-amino-terminal kinase-interacting protein 4、Cancer/testis antigen 89、CT89

+ [30]

简介

The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module (PubMed:14743216). Regulates lysosomal positioning by acting as an adapter protein which links PIP4P1-positive lysosomes to the dynein-dynactin complex (PubMed:29146937). Assists PIKFYVE selective functionality in microtubule-based endosome-to-TGN trafficking (By similarity).

关联

项与 SPAG9 相关的药物

DD3-ZD55-SPAG9

靶点

SPAG9

作用机制

SPAG9调节剂

在研机构

Second Affiliated Hospital of Soochow University

原研机构

Second Affiliated Hospital of Soochow University

在研适应症

前列腺癌

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

100 项与 SPAG9 相关的临床结果

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100 项与 SPAG9 相关的转化医学

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0 项与 SPAG9 相关的专利（医药）

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281

项与 SPAG9 相关的文献（医药）

2024-02-09·Scientific reports

Sperm-specific histone H1 in highly condensed sperm nucleus of Sargassum horneri.

Article

作者: Yu Takeuchi ; Shinya Sato ; Chikako Nagasato ; Taizo Motomura ; Shujiro Okuda ; Masahiro Kasahara ; Fumio Takahashi ; Shinya Yoshikawa

Spermatogenesis is one of the most dramatic changes in cell differentiation. Remarkable chromatin condensation of the nucleus is observed in animal, plant, and algal sperm. Sperm nuclear basic proteins (SNBPs), such as protamine and sperm-specific histone, are involved in chromatin condensation of the sperm nucleus. Among brown algae, sperm of the oogamous Fucales algae have a condensed nucleus. However, the existence of sperm-specific SNBPs in Fucales algae was unclear. Here, we identified linker histone (histone H1) proteins in the sperm and analyzed changes in their gene expression pattern during spermatogenesis in Sargassum horneri. A search of transcriptomic data for histone H1 genes in showed six histone H1 genes, which we named ShH1.1a, ShH1b, ShH1.2, ShH1.3, ShH1.4, and ShH1.5. Analysis of SNBPs using SDS-PAGE and LC-MS/MS showed that sperm nuclei contain histone ShH1.2, ShH1.3, and ShH1.4 in addition to core histones. Both ShH1.2 and ShH1.3 genes were expressed in the vegetative thallus and the male and female receptacles (the organs producing antheridium or oogonium). Meanwhile, the ShH1.4 gene was expressed in the male receptacle but not in the vegetative thallus and female receptacles. From these results, ShH1.4 may be a sperm-specific histone H1 of S. horneri.

2024-01-13·The Science of the total environment

Manganese disrupts the maturation and degradation of axonal autophagosome leading to hippocampal synaptic toxicity in mice via the activation of LRRK2 on phosphorylation of Rab10.

Article

作者: Zhuo Ma ; Kuan Liu ; Rui-Feng Zhang ; Zi-Xin Xie ; Wei Liu ; Bin Xu

Manganese (Mn) overexposure induces hippocampal synaptotoxicity by the accumulation of dysfunctional synaptic vesicles (SVs). Leucine-rich repeat kinase 2 (LRRK2) kinase activity is involved in regulating axonal transport (autophagosomal maturation) and lysosomal function. Nevertheless, it remains unclear whether Mn-induced synaptotoxicity is associated with the LRRK2-mediated disruption of autophagosomal maturation in axonal transport and the impairment of lysosomes in hippocampal neurons. Here, we established models of manganism in C57BL/6 mice and hippocampal neuronal HT22 cells to verify the role of LRRK2-mediated Rab10 phosphorylation in the Mn-induced dysfunction of autophagy- lysosomal fusion. Our results proved that Mn-induced the disorder of axonal transport and that lysosome impairments were associated with the increased recruitment of phospho-Rab10 at the axon and lysosomes. Next, we established Lrrk2-KD and LRRK2 kinase- specific inhibitor (GNE-0877, GNE) pre-treated HT22 cells to inhibit Lrrk2 gene expression and kinase activity, respectively. In Mn-treated Lrrk2-KD or GNE-pretreated normal neurons, our results indicated that lysosomal pH and integrity and autophagic flow were restored, indicating by decreased levels of phospho-Rab10 on lysosomes and JNK-interacting proteins (JIP4). In addition, GNE pretreatment could provide protection against Mn-induced synaptotoxicity in vivo, which was evidenced by the partial recovery in synaptic plasticity and synaptic damage. Thus, the Mn-induced abnormal activation of LRRK2 affected lysosomes and the recruitment of phospho-Rab10 by JIP4, which disrupted autophagosomal maturation in proximal axons and resulted in the hippocampal synaptic toxicity of mice.

2023-12-20·bioRxiv : the preprint server for biology

Heterogeneity-Preserving Discriminative Feature Selection for Subtype Discovery.

作者: Abdur Rahman M A Basher ; Caleb Hallinan ; Kwonmoo Lee

The discovery of subtypes is pivotal for disease diagnosis and targeted therapy, considering the diverse responses of different cells or patients to specific treatments. Exploring the heterogeneity within disease or cell states provides insights into disease progression mechanisms and cell differentiation. The advent of high-throughput technologies has enabled the generation and analysis of various molecular data types, such as single-cell RNA-seq, proteomic, and imaging datasets, at large scales. While presenting opportunities for subtype discovery, these datasets pose challenges in finding relevant signatures due to their high dimensionality. Feature selection, a crucial step in the analysis pipeline, involves choosing signatures that reduce the feature size for more efficient downstream computational analysis. Numerous existing methods focus on selecting signatures that differentiate known diseases or cell states, yet they often fall short in identifying features that preserve heterogeneity and reveal subtypes. To identify features that can capture the diversity within each class while also maintaining the discrimination of known disease states, we employed deep metric learning-based feature embedding to conduct a detailed exploration of the statistical properties of features essential in preserving heterogeneity. Our analysis revealed that features with a significant difference in interquartile range (IQR) between classes possess crucial subtype information. Guided by this insight, we developed a robust statistical method, termed PHet (Preserving Heterogeneity) that performs iterative subsampling differential analysis of IQR and Fisher's method between classes, identifying a minimal set of heterogeneity-preserving discriminative features to optimize subtype clustering quality. Validation using public single-cell RNA-seq and microarray datasets showcased PHet's effectiveness in preserving sample heterogeneity while maintaining discrimination of known disease/cell states, surpassing the performance of previous outlier-based methods. Furthermore, analysis of a single-cell RNA-seq dataset from mouse tracheal epithelial cells revealed, through PHet-based features, the presence of two distinct basal cell subtypes undergoing differentiation toward a luminal secretory phenotype. Notably, one of these subtypes exhibited high expression of BPIFA1. Interestingly, previous studies have linked BPIFA1 secretion to the emergence of secretory cells during mucociliary differentiation of airway epithelial cells. PHet successfully pinpointed the basal cell subtype associated with this phenomenon, a distinction that pre-annotated markers and dispersion-based features failed to make due to their admixed feature expression profiles. These findings underscore the potential of our method to deepen our understanding of the mechanisms underlying diseases and cell differentiation and contribute significantly to personalized medicine.

项与 SPAG9 相关的新闻（医药）

2022-08-19

·生物制品圈

转录因子EB(TFEB)的全方位综述

转录因子EB(TFEB)是自噬/溶酶体-核信号通路的中枢调控因子，参与能量稳态、应激反应、代谢、自噬和溶酶体生物发生等信号通路，与溶酶体储存障碍、神经退行性疾病、癌症和代谢紊乱等人类疾病有关。发表在Cell Death and Differentiation上的这篇综述概述了过去30年来TFEB研究的主要进展和最近发现的TFEB调控机制及其对人类疾病的影响，并讨论了该领域未来的研究方向和未解决的问题。FACTS：●TFEB是自噬-溶酶体生物发生的主调控因子。●TFEB参与多种信号通路，包括mTOR和ERK，并受多种上游因素的控制，包括营养物质的利用率和胁迫。●由TFEB缺陷导致的自噬-溶酶体功能受损与许多疾病有关，如溶酶体储存障碍、神经退行性疾病、癌症和代谢性疾病。●TFEB发挥自噬-溶酶体独立的功能。●鉴于TFEB在人类疾病中的重要作用，TFEB可能是临床和再生应用的一个新的治疗靶点。引言转录因子EB(TFEB)是碱性螺旋-环-螺旋亮氨酸拉链转录因子MiT/TFE家族的成员。MiT/TFE家族成员在很多细胞过程中发挥关键作用，特别是自噬-溶酶体生物发生、细胞能量稳态和代谢过程。在脊椎动物中，MiT/TFE转录因子家族由四个进化上保守的成员组成：TFEB、MITF、TFEC和TFE3(图1)。图1 原始后生动物中 MiT/TFE 蛋白及其同源物的域结构TFEB1.1 介绍TFEB所有的MiT/TFE蛋白，包括TFEB，在进化上都是保守的，它们的同源物可以在原始后生动物中找到。TFEB被认为是溶酶体生物发生的主要调节因子。TFEB通过调节自噬相关基因的表达，将自噬与溶酶体生物发生联系起来。TFEB还调节溶酶体的胞吐作用。TFEB在神经退行性疾病（如阿尔茨海默病(AD)和帕金森病(PD)、溶酶体储存障碍(LSDs)、代谢性疾病和癌症等疾病中发挥作用。图2 TFEB 蛋白的病理生理功能和重要性1.2 TFEB调控的分子机制①TFEB的细胞质和核穿梭：自噬是细胞对营养应激的一种适应，自噬激活对于维持稳态至关重要。TFEB最初主要定位于细胞质，在应对营养饥饿时转移到细胞核，饥饿后重新喂食可恢复TFEB的重新定位。TFEB上游分子（如mTORC1）被调节后，也可以诱导其核定位。此外，内质网(ER)应激、感染、线粒体损伤和炎症等也可促进TFEB的核定位。②TFEB信号：▪ mTOR依赖/不依赖的TFEB调控：TFEB的激活和细胞定位主要由蛋白相互作用和翻译后修饰(PTMs)控制。值得注意的是，TFEB的亚细胞定位受到磷酸化的严格控制（图3）。图3 TFEB 研究自发现以来的 30 年主要进展时间表mTOR激酶是一种已知的磷酸化TFEB（S122、S142和S211位点）并调节其胞内定位的主要激酶（图4）。TFEB在S142的磷酸化还由ERK2介导。图4 TFEB 结构域结构中的磷酸化位点及其调节作用最近研究还发现STUB1通过靶向磷酸化的TFEB(S142和S211)进行泛素介导的蛋白酶体降解来调节TFEB的活性（图5）。图5 mTORC1 对 TFEB 上游调控的示意图线粒体自噬是受损线粒体通过自噬降解的过程。线粒体应激可以mTOR独立的方式激活TFEB。此外，Parkin介导的TFEB在线粒体自噬诱导下的核定位受到自噬相关基因5(ATG5)下游的调控（图6）。TFEB还通过饥饿诱导的调节回路调节细胞脂质代谢，且TFEB通过调节PPARα和PGC1α的表达在调节肝脏脂质代谢中起着关键作用（图5和6）。图6 TFEB 对 PINK1/Parkin 介导的线粒体自噬的调节YAP/TFEB信号与LSDs中自噬细胞死亡和心肌病的发展有关。核内源性YAP与TFEB发生物理相互作用，促进TFEB靶基因的转录，导致自噬小体的形成，进而导致LSD中的肥厚性心肌病。▪ TFEB上游调控机构：PKCβ被激活后会磷酸化TFEB蛋白(S462、S463、S467和S469位点)，导致TFEB核定位增加（图7）。而PKC亚型PKCα和PKCδ抑制GSK3β对TFEB的磷酸化，诱导TFEB的激活和核易位（图5）。图7 TFEB 上游监管机构的示意图ERK2是细胞生长的主调节因子，在富营养条件下磷酸化TFEB。ERK2在S142位点磷酸化TFEB促进TFEB的胞质保留，而抑制ERK2促进TFEB的核定位（图5）。TFEB也可以被GSK3β在S134和S138位点上磷酸化，导致细胞质保留(图4和5）。这些位点上的TFEB磷酸化似乎将其导向溶酶体表面，在那里它与mTORC1相互作用。Akt在S467位点磷酸化TFEB，并抑制其核易位(图4和5），且Akt抑制剂治疗诱导TFEB核定位。在营养剥夺的条件下，钙调神经磷酸酶被激活，导致TFEB去磷酸化。去磷酸化的TFEB为活性形式，进入细胞核后诱导自噬-溶酶体生物发生（图7）。滤泡蛋白(FLCN)是mTORC1募集到溶酶体膜上所必需的随后被Rheb蛋白激活。活性的mTORC1磷酸化并失活TFEB，从而抑制其核定位。TFEB在溶酶体损伤过程中被激活，其激活依赖于LC3脂化。在溶酶体损伤过程中，LC3被招募到溶酶体表面并进行脂质化，之后与TRPML1相互作用，触发TFEB激活所必需的大量钙外排。赖氨酸乙酰转移酶(KATs)，如E1A结合蛋白p300(也称为KAT3B)，可以乙酰化许多控制自噬的ATG蛋白。mTOR通路通过调节p300的活性来控制TFEB的亚细胞定位。1.3 疾病中的TFEB①溶酶体储存障碍 LSD通常是由编码酶的基因缺陷引起的，这些酶参与溶酶体稳态的各个方面，并负责大分子的降解。TFEB影响LSD的分子机制，如多重硫酸酯酶缺乏症(MSD)、糖原贮积病Ⅱ型和巴登氏病。②神经退行性疾病自噬在整个AD过程中均上调。AD患者海马中miR-128表达增加会降低TFEB表达和Aβ清除率。表1总结了AD中的TFEB信号传导机制。表1 阿尔茨海默氏病的TFEB相关研究PD是由黑质多巴胺神经元的神经退行性变引起的。PD相关分子，如α-突触核蛋白(A53T和A30P突变体)、Parkin和PINK1已被报道调节自噬途径。HD是一种常染色体显性神经退行性疾病。TFEB过表达可以减少大鼠HD43纹状体细胞模型中HTT的积累。表2总结了PD和HD中的TFEB信号传导机制。表2 TFEB在神经退行性疾病中的相关研究③癌症癌细胞利用TFEB介导的自噬-溶酶体生物发生(ALB)的转录激活来实现其致癌生存，如TFEB和TFE3基因融合导致的易位肾细胞癌，儿童肾癌和肺泡软部分肉瘤。TFEB表达的改变也与胰腺导管腺癌(PDAC)的肿瘤发生和胰腺癌细胞增殖有关。TFEB缺失与口腔鳞状细胞癌(OSCC)和非小细胞肺癌(NSCLC)细胞系的迁移和侵袭性表型减少相关，这表明它可能调节细胞迁移（表3）。表3 TFEB相关的癌症研究④组织特异性功能▪ TFEB在肝脏脂质代谢中的作用：TFEB控制脂质降解细胞调节因子PGC1α的转录激活。TFEB还诱导肝脏胆汁酸的合成，抑制胆固醇积累和代谢紊乱。▪骨骼肌功能中的TFEB：TFEB是运动过程中肌肉代谢灵活性的关键中介，且FGF/TFEB/FAM134B信号表明TFEB在体内吞噬中的作用及其在体内骨骼发育中的生理相关性。TFEB在溶酶体的中心性和动力学中的作用2.1 自噬通量、溶酶体胞吐作用和溶酶体定位中的TFEBTFEB介导自噬/溶酶体介导的降解途径，包括自噬小体和自噬溶酶体的形成。TFEB还可以转录调控溶酶体的胞吐作用。TFEB/TMEM55B/JIP4通路介导的溶酶体定位可能影响溶酶体的功能。2.2自噬和溶酶体依赖性细胞死亡(LDCD)TFEB的激活通过诱导自噬依赖的细胞死亡(ADCD)在黑色素瘤和多发性骨髓瘤的增殖细胞中显示出抗癌作用。2.3溶酶体损伤中的TFEB溶酶体膜损伤可刺激TFEB的核易位，促进溶酶体生物发生。且脂化LC3对于溶酶体损伤的TFEB激活是必要的。TFEB独立于自噬-溶酶体的功能在三阴性乳腺癌(TNBC)中，TFEB对DNA损伤的反应具有一种新的溶酶体独立功能。另外，TFEB以自噬-溶酶体不依赖性的方式抑制肝细胞分化，还以一种自噬独立的方式防止肥胖和胰岛素抵抗。开放式问题●TFEB：一把具有治疗潜力的双刃剑。TFEB的激活在某些情况下是有益的，但在其他情况下可能会产生负面后果。TFEB的激活是否比抑制更重要？如何在特定的情况下避免TFEB调节？●TFEB同时具有自噬-溶酶体依赖和独立的功能。是否存在其他关键的非自噬-溶酶体生物发生功能，这些功能是否有利于治疗应用？●TFEB活性是如何在特定细胞类型的转录水平上被控制的，这是否涉及TFEB的特定转录上游调控因子？未来前景这篇综述重点关注了过去30年来TFEB研究的主要进展，以及其病理生理功能和重要性。这些进展为TFEB转录机制的重要性提供了新的见解和生物学相关性，从而突出了TFEB作为调节健康和疾病的一个强大的潜在工具。阐明TFEB治疗潜力的持续努力和进展将使我们将TFEB从基础研究推进到临床和再生应用更近一步。参考文献：Tan, A., Prasad, R., Lee, C. et al. Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease. Cell Death Differ 29, 1433–1449 (2022). https://doi.org/10.1038/s41418-022-01028-6识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。