更新于：2024-05-01

SNX1

sorting nexin 1

更新于：2024-05-01

基本信息

别名

HsT17379、MGC8664、SNX1

+ [4]

简介

Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:12198132). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) (Probable). Can sense membrane curvature and has in vitro vesicle-to-membrane remodeling activity (PubMed:19816406, PubMed:23085988). Involved in retrograde endosome-to-TGN transport of lysosomal enzyme receptors (IGF2R, M6PR and SORT1) and Shiginella dysenteria toxin stxB. Plays a role in targeting ligand-activated EGFR to the lysosomes for degradation after endocytosis from the cell surface and release from the Golgi (PubMed:12198132, PubMed:15498486, PubMed:17550970, PubMed:17101778, PubMed:18088323, PubMed:21040701). Involvement in retromer-independent endocytic trafficking of P2RY1 and lysosomal degradation of protease-activated receptor-1/F2R (PubMed:16407403, PubMed:20070609). Promotes KALRN- and RHOG-dependent but retromer-independent membrane remodeling such as lamellipodium formation; the function is dependent on GEF activity of KALRN (PubMed:20604901). Required for endocytosis of DRD5 upon agonist stimulation but not for basal receptor trafficking (PubMed:23152498).

关联

100 项与 SNX1 相关的临床结果

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100 项与 SNX1 相关的转化医学

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0 项与 SNX1 相关的专利（医药）

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302

项与 SNX1 相关的文献（医药）

2023-11-09·Autophagy

A conserved requirement for RME-8/DNAJC13 in neuronal autophagic lysosome reformation.

Article

作者: Sierra B Swords ; Nuo Jia ; Anne Norris ; Jil Modi ; Qian Cai ; Barth D Grant

Autophagosomes fuse with lysosomes, forming autolysosomes that degrade engulfed cargo. To maintain lysosomal capacity, autophagic lysosome reformation (ALR) must regenerate lysosomes from autolysosomes using a membrane tubule-based process. Maintaining lysosomal capacity is required to maintain cellular health, especially in neurons where lysosomal dysfunction has been repeatedly implicated in neurodegenerative disease. The DNA-J domain HSC70 co-chaperone RME-8/DNAJC13 has been linked to endosomal coat protein regulation and to neurological disease. We report new analysis of the requirements for the RME-8/DNAJC13 protein in neurons, focusing on intact C. elegans mechanosensory neurons, and primary mouse cortical neurons in culture. Loss of RME-8/DNAJC13 in both systems results in accumulation of grossly elongated autolysosomal tubules. Further C. elegans analysis revealed a similar autolysosome tubule accumulation defect in mutants known to be required for ALR in mammals, including mutants lacking bec-1/BECN1/Beclin1 and vps-15/PIK3R4/p150 that regulate the class III phosphatidylinositol 3-kinase (PtdIns3K) VPS-34, and dyn-1/dynamin that severs ALR tubules. Clathrin is also an important ALR regulator implicated in autolysosome tubule formation and release. In C. elegans we found that loss of RME-8 causes severe depletion of clathrin from neuronal autolysosomes, a phenotype shared with bec-1 and vps-15 mutants. We conclude that RME-8/DNAJC13 plays a previously unrecognized role in ALR, likely affecting autolysosome tubule severing. Additionally, in both systems, loss of RME-8/DNAJC13 reduced macroautophagic/autophagic flux, suggesting feedback regulation from ALR to autophagy. Our results connecting RME-8/DNAJC13 to ALR and autophagy provide a potential mechanism by which RME-8/DNAJC13 could influence neuronal health and the progression of neurodegenerative disease.Abbreviation: ALR, autophagic lysosome reformation; ATG-13/EPG-1, AuTophaGy (yeast Atg homolog)-13; ATG-18, AuTophaGy (yeast Atg homolog)-18; AV, autophagic vacuole; CLIC-1, Clathrin Light Chain-1; EPG-3, Ectopic P Granules-3; EPG-6, Ectopic P Granules-6; LGG-1, LC3, GABARAP and GATE-16 family-1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; PD, Parkinson disease; PtdIns3P, phosphatidylinositol-3-phosphate; PtdIns(4,5)P₂, phosphatidylinositol-4,5-bisphosphate; RME-8, Receptor Mediated Endocytosis-8; SNX-1, Sorting NeXin-1; VPS-34, related to yeast Vacuolar Protein Sorting factor-34.

2023-08-30·The Plant cell

The plant-unique protein DRIF1 coordinates with SNX1 to regulate membrane protein homeostasis.

Article

作者: Ying Zhu ; Qiong Zhao ; Wenhan Cao ; Shuxian Huang ; Changyang Ji ; Wenxin Zhang ; Marco Trujillo ; Jinbo Shen ; Liwen Jiang

Membrane protein homeostasis is fine-tuned by the cellular pathways for vacuolar degradation and recycling, which ultimately facilitate plant growth and cell-environment interactions. The endosomal sorting complex required for transport (ESCRT) machinery plays important roles in regulating intraluminal vesicle (ILV) formation and membrane protein sorting to vacuoles. We previously showed that the plant-specific ESCRT component FYVE DOMAIN PROTEIN REQUIRED FOR ENDOSOMAL SORTING1 (FREE1) performs multiple functions in plants, although the underlying mechanisms remain elusive. In this study, we performed a suppressor screen of the FREE1-RNAi mutant and identified and characterized two suppressor of free1 (sof) mutants in Arabidopsis (Arabidopsis thaliana). These mutants, sof10 and sof641, result in a premature stop codon or a missense mutation in AT5G10370, respectively. This gene was named DEAH and RING domain-containing protein as FREE1 suppressor 1 (DRIF1). DRIF1 has a homologous gene, DRIF2, in the Arabidopsis genome with 95% identity to DRIF1. The embryos of drif1 drif2 mutants arrested at the globular stage and formed enlarged multivesicular bodies (MVBs) with an increased number of ILVs. DRIF1 is a membrane-associated protein that coordinates with retromer component sorting nexin 1 (SNX1) to regulate PIN-FORMED2 (PIN2) recycling to the plasma membrane. Altogether, our data demonstrate that DRIF1 is a unique retromer interactor that orchestrates FREE1-mediated ILV formation of MVBs and vacuolar sorting of membrane proteins for degradation in plants.

2023-07-15·International journal of molecular sciences

In Silico Identification and Analysis of Proteins Containing the Phox Homology Phosphoinositide-Binding Domain in Kinetoplastea Protists: Evolutionary Conservation and Uniqueness of Phox-Homology-Domain-Containing Protein Architectures.

Article

作者: Marina Petsana ; Ahmed F Roumia ; Pantelis G Bagos ; Haralabia Boleti ; Georgia G Braliou

Kinetoplastea are free living and parasitic protists with unique features among Eukaryota. Pathogenic Kinetoplastea parasites (i.e., Trypanosoma and Leishmania spp.) undergo several developmental transitions essential for survival in their hosts. These transitions require membrane and cytoskeleton reorganizations that involve phosphoinositides (PIs). Phospholipids like PIs are key regulators of vital functions in all eukaryotes including signal transduction, protein transport and sorting, membrane trafficking, and cytoskeleton and membrane remodeling. A large repertoire of PI-metabolizing enzymes and PI-binding proteins/effectors carrying distinct PI-binding modules like the PX (phox homology) module could play significant roles in the life and virulence of pathogenic Kinetoplastea. The aim of this study was to retrieve the entire spectrum of Kinetoplastea protein sequences containing the PX module (PX-proteins), predict their structures, and identify in them evolutionary conserved and unique traits. Using a large array of bioinformatics tools, protein IDs from two searches (based on PFam's pHMM for PX domain (PF00787)) were combined, aligned, and utilized for the construction of a new Kinetoplastea_PX pHMM. This three-step search retrieved 170 PX-protein sequences. Structural domain configuration analysis identified PX, Pkinase, Lipocalin_5, and Vps5/BAR3-WASP domains and clustered them into five distinct subfamilies. Phylogenetic tree and domain architecture analysis showed that some domain architectures exist in proteomes of all Kinetoplastea spp., while others are genus-specific. Finally, amino acid conservation logos of the Kinetoplastea spp. and Homo sapiens PX domains revealed high evolutionary conservation in residues forming the critical structural motifs for PtdIns3P recognition. This study highlights the PX-Pkinase domain architecture as unique within Trypanosoma spp. and forms the basis for a targeted functional analysis of Kinetoplastea PX-proteins as putative targets for a rational design of anti-parasitic drugs.

项与 SNX1 相关的新闻（医药）

2024-01-18

·奇点网

从脑脊液识出阿尔茨海默病的5个“分身”！

*仅供医学专业人士阅读参考阿尔茨海默病（AD）的病理特征包括大脑中的β-淀粉样蛋白沉积和tau蛋白纤维缠结，即当前药物研发的两个重点方向。就在本月初，仑卡奈单抗在中国获批上市，成为首款在国内上市的治疗阿尔茨海默病的抗Aβ药物。但是越来越多的研究表明，AD的发病机制复杂，具有异质性，如果仅仅集中火力攻于β-淀粉样蛋白沉淀和tau蛋白异常，不同患者的临床获益可能会有很大差异。荷兰阿姆斯特丹自由大学的Betty M. Tijms等人通过对609名参与者的脑脊液进行蛋白质组学分析，揭示5种AD分子亚型。这些亚型分别以神经元增生、先天免疫异常激活、RNA失调、脉络丛功能障碍和血脑屏障功能障碍为特点，具有不同的遗传特征、临床结局、生存时间以及脑皮质萎缩特征[1]。这项研究成果强调了AD个体化治疗的重要性，文章于近日发表在《自然·衰老》期刊上。论文首页脑脊液环绕在大脑和脊髓周围，充当缓冲和保护作用，同时也参与营养物质和废物的运输。位置上的接近，使得脑脊液中的成分变化能够直接反映大脑的健康状况。 2020年，Betty M. Tijms等人基于脑脊液蛋白质组学确定了3种AD分子亚型[2]。如今蛋白质组学技术日益改进，研究者们认为是时候对AD亚型的描述进行完善。此次，他们共获取609名参与者的脑脊液样本。其中419人经生物标志物检测诊断为不同阶段的AD患者，包括认知正常、轻度认知障碍（MCI）、痴呆症；其他人具有正常认知能力且未被诊断为AD。总体来看，有1058种脑脊液蛋白质在非AD患者与AD患者之间差异表达。研究者们进一步采用非负矩阵分解（NMF）的方法来对AD患者进行聚类分析，从而根据脑脊液蛋白质组学特征将AD患者分为5种亚型。 5种亚型的脑脊液蛋白质组学特征亚型1的特点为神经元增生。表达上调的蛋白质与神经元可塑性相关，如突触组装、轴突引导、神经元生成、胶质细胞生成等生理过程。与其相关的AD遗传变异是TREM2 R47H。亚型2的特点为先天免疫异常激活。显示小胶质细胞特异性蛋白水平升高，与先天免疫激活有关。与其相关的AD遗传变异是IDUA、CLNK和SCIMP。亚型3的特点为RNA失调（RNA dysregulation）。表达上调的蛋白质参与细胞骨架组成、轴突运输、蛋白酶体功能、蛋白质折叠，尤其是异质核核糖核蛋白（hnRNP）等RNA结合蛋白，表达明显上调。与其相关的AD遗传变异是BIN1、TREM2 R62H、SPDYE3、SNX1、KAT8。亚型4的特点为脉络丛（产生脑脊液的地方）功能障碍。表达上调的蛋白质中有45%参与脉络丛发育，涉及细胞粘附、SMAD通路；此外还有小胶质细胞等免疫细胞特异性蛋白水平升高。与其相关的AD遗传变异是ABCA7、PICALM、IL-34、CLNK。亚型5的特点为血脑屏障功能障碍。白蛋白、纤维蛋白原、纤溶酶原和凝血酶等本不该存在于大脑的蛋白质，在这类亚型患者的脑脊液中水平异常升高，表明来自血液的蛋白质趁血脑屏障受损渗入大脑；与血液凝固、B细胞介导的免疫反应、急性炎症反应等生理过程相关的蛋白质表达上调。与其相关的AD遗传变异是IL-34、ECHDC3、APP。其中，亚型1、2、3患者的脑脊液tau蛋白水平显著升高，而亚型4、5患者的脑脊液tau蛋白水平大多为正常。相比于对照组，所有AD亚型的APOE e4基因变异水平、AD多基因风险评分（PRS）均更高。亚型5的APOE e4基因变异携带者比例为最高。不同亚型由MCI进展痴呆症的风险不同，亚型2、5的风险最高，亚型4的风险最低。不同亚型的生存情况不同，亚型3患者的平均生存时间最短，为5.6年；亚型1患者的平均生存时间最长，为8.9年。此外，磁共振成像（MRI）扫描结果显示，不同亚型的脑皮质萎缩程度。与亚型1、2、5相比，亚型2、4具有更严重的脑皮质萎缩现象。 5种亚型的MRI图像和临床结局最后，研究者们利用来自欧洲、美国等多个不同国家的多组队列进行验证，通过脑脊液蛋白质组学鉴定其AD亚型。结果观察到，与上面的发现队列中的比例相近，27.9%的AD患者为亚型1，35.5%为亚型2，5.8%为亚型3，17.1%为亚型4，16.6%为亚型5，且特征相符。多国大型队列中验证5种AD亚型这些结果意味着，基于脑脊液确定患者AD亚型或有助于选择个体进行特定的治疗。例如，亚型1的患者可能受益于针对TREM2的治疗，亚型2需要先天免疫抑制剂，亚型3需要恢复RNA功能，亚型4可能从抑制单核细胞浸润中受益，而亚型5需要针对脑血管的治疗[3]。同时，某些治疗产生的副作用也可能取决于亚型。例如在抗体治疗，虽然抗体可能更容易穿过亚型5患者的血脑屏障，但这些人发生脑出血的风险也会增加[3]。总之，提到AD，我们总会下意识将其认定为单一一种疾病进行治疗。而这项研究不仅揭示了AD在分子层面的复杂性，也为AD的个性化医疗提供了新的视角。随着研究的深入，我们有望更好地理解AD的复杂机制，并为患者提供更有效的治疗方案。参考文献：[1]Tijms, B.M., Vromen, E.M., Mjaavatten, O. et al. Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles. Nat Aging (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s43587-023-00550-7[2]Tijms BM, Gobom J, Reus L, Jansen I, Hong S, Dobricic V, Kilpert F, Ten Kate M, Barkhof F, Tsolaki M, Verhey FRJ, Popp J, Martinez-Lage P, Vandenberghe R, Lleó A, Molinuevo JL, Engelborghs S, Bertram L, Lovestone S, Streffer J, Vos S, Bos I; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Blennow K, Scheltens P, Teunissen CE, Zetterberg H, Visser PJ. Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics. Brain. 2020 Dec 1;143(12):3776-3792. doi: 10.1093/brain/awaa325本文作者丨张艾迪

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