更新于：2024-05-01

SNX5

sorting nexin 5

更新于：2024-05-01

基本信息

别名

SNX5、sorting nexin 5、Sorting nexin-5

简介

Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) (PubMed:15561769). 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). Does not have in vitro vesicle-to-membrane remodeling activity (PubMed:23085988). Involved in retrograde transport of lysosomal enzyme receptor IGF2R (PubMed:17148574, PubMed:18596235). May function as link between endosomal transport vesicles and dynactin (Probable). Plays a role in the internalization of EGFR after EGF stimulation (Probable). Involved in EGFR endosomal sorting and degradation; the function involves PIP5K1C isoform 3 and is retromer-independent (PubMed:23602387). Together with PIP5K1C isoform 3 facilitates HGS interaction with ubiquitinated EGFR, which initiates EGFR sorting to intraluminal vesicles (ILVs) of the multivesicular body for subsequent lysosomal degradation (Probable). Involved in E-cadherin sorting and degradation; inhibits PIP5K1C isoform 3-mediated E-cadherin degradation (PubMed:24610942). Plays a role in macropinocytosis (PubMed:18854019, PubMed:21048941).

关联

100 项与 SNX5 相关的临床结果

登录后查看更多信息

100 项与 SNX5 相关的转化医学

登录后查看更多信息

0 项与 SNX5 相关的专利（医药）

登录后查看更多信息

项与 SNX5 相关的文献（医药）

2024-03-04·The Journal of cell biology

Rab32 family proteins regulate autophagosomal components recycling.

Article

作者: Zhe Wu ; Huilin Que ; Chuangpeng Li ; Li Yan ; Shixuan Wang ; Yueguang Rong

In autophagy, autophagosomes deliver the lumenal contents to lysosomes for degradation via autophagosome-lysosome fusion. In contrast, autophagosome outer membrane components were recycled via autophagosomal components recycling (ACR), which is mediated by the recycler complex. The recycler complex, composed of SNX4, SNX5, and SNX17, cooperate with the dynein-dynactin complex to mediate ACR. However, how ACR is regulated remains unknown. Here, we found that Rab32 family proteins localize to autolysosomes and are required for ACR, rather than other autophagosomal or lysosomal Rab proteins. The GTPase activity of Rab32 family proteins, governed by their guanine nucleotide exchange factor and GTPase-activating protein, plays a key role in regulating ACR. This regulation occurs through the control of recycler complex formation, as well as the connection between the recycler-cargo and dynactin complex. Together, our study reveals an unidentified Rab32 family-dependent regulatory mechanism for ACR.

2023-11-28·Journal of biomedical research

Structural determinants specific for retromer protein sorting nexin 5 in regulating subcellular retrograde membrane trafficking.

Article

作者: Qing Chen ; Meiheng Sun ; Xu Han ; Hongfei Xu ; Yongjian Liu

The endosomal trafficking of signaling membrane proteins, such as receptors, transporters and channels, is mediated by the retromer-mediated sorting machinery, composed of a cargo-selective vacuolar protein sorting trimer and a membrane-deforming subunit of sorting nexin proteins. Recent studies have shown that the isoforms, sorting nexin 5 (SNX5) and SNX6, have played distinctive regulatory roles in retrograde membrane trafficking. However, the molecular insight determined functional differences within the proteins remains unclear. We reported that SNX5 and SNX6 had distinct binding affinity to the cargo protein vesicular monoamine transporter 2 (VMAT2). SNX5, but not SNX6, specifically interacted with VMAT2 through the Phox domain, which contains an alpha-helix binding motif. Using chimeric mutagenesis, we identified that several key residues within this domain were unique in SNX5, but not SNX6, and played an auxiliary role in its binding to VMAT2. Importantly, we generated a set of mutant SNX6, in which the corresponding key residues were mutated to those in SNX5. In addition to the gain in binding affinity to VMAT2, their overexpression functionally rescued the altered retrograde trafficking of VMAT2 induced by siRNA-mediated depletion of SNX5. These data strongly suggest that SNX5 and SNX6 have different functions in retrograde membrane trafficking, which is determined by the different structural elements within the Phox domain of two proteins. Our work provides a new information on the role of SNX5 and SNX6 in the molecular regulation of retrograde membrane trafficking and vesicular membrane targeting in monoamine neurotransmission and neurological diseases.

2023-09-01·Heliyon

Hsa_circRNA_0084043 promoting tumorigenesis in glioma through miR-577 sponging.

Article

作者: Jin Qian ; Chunyan Chen ; Changping Zhao ; Xing Xu ; Yingna Xu ; Yong Zhang ; Chunfa Qian

Circular RNAs (circRNAs) are important non-coding RNAs (ncRNAs) involved in the development of multiple human diseases, especially cancers. circRNA_0084043 is significantly involved in the progression of melanoma. However, whether circRNA_0084043 is associated with glioma remains unknown. In this study, the upregulation of circRNA_0084043 in glioma and the association between circRNA_0084043 and glioma grade were identified. Our results showed that circRNA_0084043 is significantly involved in the proliferative, migratory, and invasive capacities of glioma cells. The results obtained from starBase, luciferase reporter assays, RNA immunoprecipitation assays, and RNA pull-down assays demonstrated that circRNA_0084043 acts as a direct sponge for miR-577. TargetScan algorithm was used to identify potential miR-577 targets, it was found that sorting nexin 5 (SNX5) is a candidate bound to miR-577. Finally, cell experiments testified that circRNA_0084043 enhanced growth, migration and invasion of glioma through the regulation of miR-577-mediated SNX5. Taken together, we concluded that circRNA_0084043 in the miR-577/SNX5 axis can be used as a candidate target for glioma therapy.

项与 SNX5 相关的新闻（医药）

2024-02-18

·梅斯医学

“吃得越少，活得越久，脑子越好”的原因找到了！Nature子刊：限制饮食能延寿和护脑，背后关键环节在于...

饮食/热量限制（Dietary/Caloric Restriction）能延缓衰老并非新闻。自古以来，人们便意识到了限制饮食或热量的重要性。《黄帝内经》中有这样一句养生之道：食饮有节，起居有常，不妄作劳，故能形与神俱，而尽终其天年，度百岁乃去。东晋时期著名医生葛洪曾言，不欲极饥而食，食不过饱。现在人们最常提到的“饭吃八分饱”的说法，也与其有着异曲同工之处。饮食/热量限制（DR/CR），是指在满足必需营养素（如必需氨基酸、维生素、必需脂肪酸等）摄取的情况下，减少能量摄入。从现代科学来看，饮食限制能延寿并非“空穴来风”，目前已在多物种中观察到其抗衰老、延寿命的作用，包括酵母、啮齿动物、非人类灵长动物，甚至人类身上。在现实生活中，衰老往往伴随着“认知能力下降”现象的发生。于是，研究者开始思考，既然饮食限制能够延缓物种的衰老，是否也同样能起到保护大脑的作用呢？最近，来自美国巴克衰老研究所的研究团队回答了上述问题，并从细胞学机制层面找到了饮食限制能延长寿命和保护大脑的关键一环——mtd/OXR1基因。具体来说，在饮食限制的条件下，mtd/OXR1可以维持逆转录酶，从而保护神经健康和延缓大脑衰老。该研究发表在Nature Communications上。https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-023-44343-3研究者早已观察到，人耐氧化性能蛋白（OXR1）基因具有着重要作用——如果基因发生变异，会导致小脑萎缩、张力减退、语言发育迟缓和癫痫发作等一系列疾病。相反，在肌萎缩侧索硬化症（ALS）的小鼠模型中，OXR1基因的过表达则能够提高存活率。那么，在神经缺陷和过早死亡的发生过程中，OXR1基因是否发挥了保护作用？又是如何发挥的呢？为了回答这一问题，研究者扫首先描了160种具有不同遗传背景的果蝇，并在自由进食（AL）和DR（约正常饮食的10%）的条件下进行喂养。在测试了果蝇寿命后，定位到了5个与“DR诱导的长寿”显著相关的基因，它们均具有特定的遗传变异。但在上述5个基因中，仅仅铁氧还原蛋白（Fdxh）和mustard（mtd）有人类同源基因，分别对应着铁氧还原蛋白2和OXR1。对比发现，由Act5c-GS-Gal4驱动的全身mtdRNA干扰会导致DR特异性的寿命缩短，而FdxhRNA干扰则无法诱导该现象。也就是说，mtd表达在DR介导的长寿过程中发挥着重要作用。于是，在这两个基因中，研究者选择了与人类和小鼠OXR1相对应的基因mtd，而后续研究将基于mtd深入展开。DR条件下延长的寿命需要基于mtd的表达有意思的是，研究者在果蝇的头部观察到，DR条件下的mtd mRNA表达量增加了7倍。如果能一直坚持DR，整个生命周期中的mtd表达均显著增加。也就是说，饮食限制能够增加果蝇神经元中mtd的表达。但与之相反，当采用组成型活性elav-Gal4驱动神经元mtd mRNA干扰后，无论是采用何种饮食模式，甚至DR，均会诱导果蝇发育缺陷的发生以及严重的寿命缩短。Mtd/OXR1中的TLDc结构域发挥着保护神经的作用。于是，研究者进一步在不携带mtd等位基因的果蝇神经元中过表达了缩减的人OXR1基因（hOXR1OE），观察到果蝇“找回了”丢失的寿命和DR反应。由此可见，神经元mtd的表达是DR介导的寿命延长过程中必不可少的一环，如果将其敲除则会诱发严重的发育缺陷以及寿命缩短。敲除mtd基因会导致寿命的缩短利用公开的ChIP-seq数据，研究者找到了DR中调节mtd表达的关键点——Traffic Jam（TJ）。具体来说，ChIP-seq数据显示基因座上存在CCCTC结合因子（CTCF）和TJ的重要结合信号。其中，诱导性神经元ctcfRNA干扰增加了mtd的表达，而tjRNA干扰则导致DR条件下所有mtd转录表达的降低以及寿命的缩短。事实上，饮食限制主要限制了整体蛋白质摄入量，进一步的验证显示，蛋白质限制诱导的mtd增加受到TJ的调控，从而延长了果蝇的寿命；但在正常饮食条件下，mtd表达则会受到CTCF的影响而被抑制。不过，这些效应只影响变异位点和TJ/CTCF结合位点下游的较短转录本。研究者解释道，体内营养相关成分的增加并非好事儿，反而可能会带来一定的健康损害，比如逆转录酶失调，甚至进一步缩短了寿命。在“向下”找到了影响mtd表达的关键因素之后，接下来“向上”探索mtd影响寿命的具体机制。这个过程究竟是如何实现的呢？研究者分析了与人OXR1共表达模式相似的前50个基因的基因本体（GO）术语，并对人成纤维细胞的OXR1和囊泡转运细胞器标记物进行了共同染色，包括溶酶体、核内体、高尔基体、内质网和线粒体。进一步的实验观察到，OXR1染色与内体标志物RAB7高度重叠。这时候，如果对神经元mtdRNA进行干扰，会发现果蝇体内Atg8a-II水平有所增加，即自噬体形成的标志物增加。研究者解释道，由于内吞蛋白和脂质的不当运输，内体中逆运复合体（retromer）功能障碍会导致溶酶体功能障碍，以及自噬体形成的增加。因此，可以推测，OXR1具有维持逆运复合体功能的作用。果不其然，当研究者对果蝇体内的神经元mtdRNA和tjRNA进行干扰时，逆运复合体蛋白水平被显著降低了，证明上述推测是正确的。事实上，对于健康的神经元来说，逆运复合体的维持是必不可少的；相反，当缺失逆运复合体蛋白时，则会诱导神经退行性疾病的发生。所以，mtd基因之所以能发挥抗衰和保护神经的作用，是因为它参与了逆运复合体功能的维持。mtd与逆运复合体之间的相互作用最后一步，回归人体——mtd/OXR1表达是否能够发挥防止神经退行性疾病和阿尔茨海默症发生的作用呢？利用人类组学数据集，研究者观察到，在丰度水平与OXR1基因呈正相关的蛋白质和受年龄影响的基因中，有83个基因存在重叠。进一步对数据集重叠基因进行KEGG通路分析，结果显示，与年龄相关的神经退行性疾病（包括阿尔茨海默症、亨廷顿氏症、帕金森病等）均出现了显著的富集。此外，研究者观察到，低水平的OXR1、VPS35、SNX5和RAB7A与阿尔茨海默症的诊断、记忆力和病理评分低下有关，而这些都是人OXR1和逆运复合体相关蛋白。相反，如果过表达了OXR1或逆运复合体，则能够挽救与阿尔茨海默症以及tau病理相关的表型。正如先前提到的那样，逆运复合体功能障碍与年龄相关性退行性神经疾病（比如阿尔茨海默症）之间有着紧密联系，尤其是在疾病进展的转运和突触功能的维持。鉴于OXR1与逆运复合体之间的关系，OXR1及其蛋白网络是减缓人类和果蝇衰老和与年龄相关的神经退行性疾病的关键调节剂。综上所述，本研究发现了一个重要基因mtd/OXR1——在间歇性禁食或者卡路里限制等营养限制的策略中，mtd/OXR1基因水平会有所提高，进一步激活了逆运复合体功能，发挥出维持神经元功能、延缓大脑衰老以及寿命延长等多种作用，对大脑健康产生正向影响。本研究的共同通讯作者Kenneth Wilson还强调了另一个观点“饮食会影响人体内所有的过程”。所以，只要你努力坚持健康饮食方式，身体是不会“辜负”你的，而且这种影响会比你想象得更大。总结来说，吃得少，活得久，脑更灵。春节想必大家一定吃了不少吧，从今天开始可以加入“少吃”行列了哦参考资料：[1]Wilson, K.A., Bar, S., Dammer, E.B. et al. OXR1 maintains the retromer to delay brain aging under dietary restriction. Nat Commun 15, 467 (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-023-44343-3撰文 | Swagpp编辑 | Swagpp版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。点击下方「阅读原文」立刻下载梅斯医学APP！