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Statistical modeling of mRNP transport in dendrites: A comparative analysis of β-actin and Arc mRNP dynamics. 树突中mRNP转运的统计模型:β-肌动蛋白和Arc mRNP动力学的比较分析。
IF 4.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-08-06 DOI: 10.1111/tra.12913
Hyerim Ahn, Xavier Durang, Jae Youn Shim, Gaeun Park, Jae-Hyung Jeon, Hye Yoon Park

Localization of messenger RNA (mRNA) in dendrites is crucial for regulating gene expression during long-term memory formation. mRNA binds to RNA-binding proteins (RBPs) to form messenger ribonucleoprotein (mRNP) complexes that are transported by motor proteins along microtubules to their target synapses. However, the dynamics by which mRNPs find their target locations in the dendrite have not been well understood. Here, we investigated the motion of endogenous β-actin and Arc mRNPs in dissociated mouse hippocampal neurons using the MS2 and PP7 stem-loop systems, respectively. By evaluating the statistical properties of mRNP movement, we found that the aging Lévy walk model effectively describes both β-actin and Arc mRNP transport in proximal dendrites. A critical difference between β-actin and Arc mRNPs was the aging time, the time lag between transport initiation and measurement initiation. The longer mean aging time of β-actin mRNP (~100 s) compared with that of Arc mRNP (~30 s) reflects the longer half-life of constitutively expressed β-actin mRNP. Furthermore, our model also permitted us to estimate the ratio of newly generated and pre-existing β-actin mRNPs in the dendrites. This study offers a robust theoretical framework for mRNP transport, which provides insight into how mRNPs locate their targets in neurons.

信使核糖核酸(信使核糖核酸)在树突中的定位对于调节长期记忆形成过程中的基因表达至关重要。mRNA与RNA结合蛋白(RBP)结合,形成信使核糖核蛋白(mRNP)复合物,由运动蛋白沿微管转运至其靶突触。然而,mRNP在树突中找到目标位置的动力学尚未得到很好的理解。在这里,我们分别使用MS2和PP7干环系统研究了分离的小鼠海马神经元中内源性β-肌动蛋白和Arc-mRNPs的运动。通过评估mRNP运动的统计特性,我们发现衰老的Lévy行走模型有效地描述了近端树突中的β-肌动蛋白和Arc mRNP转运。β-肌动蛋白和Arc-mRNPs之间的关键差异是老化时间、转运起始和测量起始之间的时间滞后。β-肌动蛋白mRNP(~100 s) 与Arc mRNP(~30 s) 反映了组成型表达的β-肌动蛋白mRNP的半衰期更长。此外,我们的模型还允许我们估计树突中新产生和预先存在的β-肌动蛋白mRNPs的比例。这项研究为mRNP转运提供了一个强大的理论框架,深入了解了mRNP如何在神经元中定位其靶点。
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引用次数: 0
Anterograde trafficking of Toll-like receptors requires the cargo sorting adaptors TMED-2 and 7. Toll样受体的反向贩运需要货物分拣适配器TMED-2和7。
IF 4.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-07-26 DOI: 10.1111/tra.12912
Julia E J Holm, Sandro G Soares, Martyn F Symmons, Afiqah Saleh Huddin, Martin C Moncrieffe, Nicholas J Gay

Toll-Like Receptors (TLRs) play a pivotal role in immunity by recognising conserved structural features of pathogens and initiating the innate immune response. TLR signalling is subject to complex regulation that remains poorly understood. Here we show that two small type I transmembrane receptors, TMED2 and 7, that function as cargo sorting adaptors in the early secretory pathway are required for transport of TLRs from the ER to Golgi. Protein interaction studies reveal that TMED7 interacts with TLR2, TLR4 and TLR5 but not with TLR3 and TLR9. On the other hand, TMED2 interacts with TLR2, TLR4 and TLR3. Dominant negative forms of TMED7 suppress the export of cell surface TLRs from the ER to the Golgi. By contrast TMED2 is required for the ER-export of both plasma membrane and endosomal TLRs. Together, these findings suggest that association of TMED2 and TMED7 with TLRs facilitates anterograde transport from the ER to the Golgi.

Toll样受体(TLRs)通过识别病原体的保守结构特征和启动先天免疫反应,在免疫中发挥着关键作用。TLR信号传导受到复杂的调控,但人们对此知之甚少。在这里,我们发现两种小的I型跨膜受体,TMED2和7,在早期分泌途径中作为货物分拣适配器发挥作用,是将TLR从内质网转运到高尔基体所必需的。蛋白质相互作用研究表明,TMED7与TLR2、TLR4和TLR5相互作用,但与TLR3和TLR9不相互作用。另一方面,TMED2与TLR2、TLR4和TLR3相互作用。TMED7的显性阴性形式抑制细胞表面TLR从内质网向高尔基体的输出。相比之下,TMED2是质膜和内体TLR的ER输出所必需的。总之,这些发现表明TMED2和TMED7与TLRs的结合促进了从ER到高尔基体的顺行运输。
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引用次数: 0
Combination of hydrophobicity and codon usage bias determines sorting of model K+ channel protein to either mitochondria or endoplasmic reticulum. 疏水性和密码子使用偏差的组合决定了模型K+通道蛋白向线粒体或内质网的分选。
IF 4.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-08-14 DOI: 10.1111/tra.12915
Anja J Engel, Steffen Paech, Markus Langhans, James L van Etten, Anna Moroni, Gerhard Thiel, Oliver Rauh

When the K+ channel-like protein Kesv from Ectocarpus siliculosus virus 1 is heterologously expressed in mammalian cells, it is sorted to the mitochondria. This targeting can be redirected to the endoplasmic reticulum (ER) by altering the codon usage in distinct regions of the gene or by inserting a triplet of hydrophobic amino acids (AAs) into the protein's C-terminal transmembrane domain (ct-TMD). Systematic variations in the flavor of the inserted AAs and/or its codon usage show that a positive charge in the inserted AA triplet alone serves as strong signal for mitochondria sorting. In cases of neutral AA triplets, mitochondria sorting are favored by a combination of hydrophilic AAs and rarely used codons; sorting to the ER exhibits the inverse dependency. This propensity for ER sorting is particularly high when a common codon follows a rarer one in the AA triplet; mitochondria sorting in contrast is supported by codon uniformity. Since parameters like positive charge, hydrophobic AAs, and common codons are known to facilitate elongation of nascent proteins in the ribosome the data suggest a mechanism in which local changes in elongation velocity and co-translational folding in the ct-TMD influence intracellular protein sorting.

当来自Ectocarpus siliculosus病毒1的K+通道样蛋白Kesv在哺乳动物细胞中异源表达时,它被分选到线粒体中。这种靶向可以通过改变基因不同区域的密码子使用或通过将疏水性氨基酸(AAs)的三联体插入蛋白质的C末端跨膜结构域(ct-TMD)而重定向到内质网(ER)。插入的AA的风味和/或其密码子使用的系统变化表明,插入的AA三联体中的正电荷单独作为线粒体分选的强信号。在中性AA三联体的情况下,亲水性AA和很少使用的密码子的组合有利于线粒体分选;对ER的排序表现出相反的依赖性。当AA三联体中一个常见密码子跟随一个罕见密码子时,这种ER排序的倾向特别高;相比之下,线粒体的排序得到了密码子一致性的支持。由于已知正电荷、疏水性AAs和常见密码子等参数有助于核糖体中新生蛋白质的延伸,因此数据表明,ct-TMD中延伸速度和共翻译折叠的局部变化影响细胞内蛋白质分选的机制。
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引用次数: 0
Dynamic tandem proximity-based proteomics-Protein trafficking at the proteome-scale. 基于动态串联邻近度的蛋白质组学蛋白质组学规模的蛋白质运输。
IF 4.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-11-01 Epub Date: 2023-08-15 DOI: 10.1111/tra.12914
Eric Chevet, Maria Antonietta De Matteis, Eeva-Liisa Eskelinen, Hesso Farhan

TransitID is a new methodology based on proximity labeling allowing for the study of protein trafficking a the proteome scale.

TransitID是一种基于邻近标记的新方法,可用于蛋白质组规模的蛋白质运输研究。
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引用次数: 0
The role of extracellular vesicles in iron homeostasis and ferroptosis: Focus on musculoskeletal diseases. 细胞外囊泡在铁稳态和铁下垂中的作用:聚焦于肌肉骨骼疾病。
IF 4.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1111/tra.12905
Zhiwei Liao, Bide Tong, Zixuan Ou, Junyu Wei, Ming Lei, Cao Yang
Iron homeostasis is crucial for maintaining proper cellular function, and its disruption is considered one of the pathogenic mechanisms underlying musculoskeletal diseases. Under conditions of oxidative stress, the accumulation of cellular iron overload and lipid peroxidation can lead to ferroptosis. Extracellular vesicles (EVs), serving as mediators in the cell‐to‐cell communication, play an important role in regulating the outcome of cell ferroptosis. Growing evidence has proven that EV biogenesis and secretion are tightly associated with cellular iron export. Furthermore, different sources of EVs deliver diverse cargoes to bring about phenotypic changes in the recipient cells, either activating or inhibiting ferroptosis. Thus, delivering therapies targeting ferroptosis through EVs may hold significant potential for treating musculoskeletal diseases. This review aims to summarize current knowledge on the role of EVs in iron homeostasis and ferroptosis, as well as their therapeutic applications in musculoskeletal diseases, and thereby provide valuable insights for both research and clinical practice.
铁稳态对维持正常的细胞功能至关重要,其破坏被认为是肌肉骨骼疾病的致病机制之一。在氧化应激条件下,细胞铁超载和脂质过氧化的积累可导致铁下垂。细胞外囊泡(Extracellular vesicles, ev)作为细胞间通讯的介质,在调节细胞铁凋亡的结果中发挥重要作用。越来越多的证据表明,EV的生物发生和分泌与细胞铁输出密切相关。此外,不同来源的ev提供不同的货物,在受体细胞中引起表型变化,激活或抑制铁下垂。因此,通过ev提供针对铁下垂的治疗可能具有治疗肌肉骨骼疾病的巨大潜力。本文旨在综述ev在铁稳态和铁凋亡中的作用,以及它们在肌肉骨骼疾病中的治疗应用,从而为研究和临床实践提供有价值的见解。
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引用次数: 0
Crucial roles of Rab22a in endosomal cargo recycling. Rab22a在内体货物循环中的关键作用。
IF 4.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1111/tra.12907
Lingjie Kong, Shenghao Huang, Yuxuan Bao, Yingtong Chen, Chunyan Hua, Sheng Gao

Endosomal cargo recycling lies at the heart of subcellular trafficking processes under the management of several Ras-related GTP-binding proteins (Rabs) which are coordinated by their upstream regulators and require their downstream effectors to display their functions. In this regard, several Rabs have been well-reviewed except Rab22a. Rab22a is a crucial regulator of vesicle trafficking, early endosome and recycling endosome formation. Notably, recent studies demonstrated the immunological roles of Rab22a, which are closely associated with cancers, infection and autoimmune disorders. This review provides an overview of the regulators and effectors of Rab22a. Also, we highlight the current knowledge of the role of Rab22a in endosomal cargo recycling, including the biogenesis of recycling tubules with the help of a complex with Rab22a at its core, and how different internalized cargo chooses different recycling routes thanks to the cooperation of Rab22a, its effectors and its regulators. Of note, contradictions and speculation related to endosomal cargo recycling that Rab22a brings impacts on are also discussed. Finally, this review endeavors to briefly introduce the various events impacted by Rab22a, particularly focusing on the commandeered Rab22a-associated endosomal maturation and endosomal cargo recycling, in addition to the extensively investigated oncogenic role of Rab22a.

在几种ras相关的gtp结合蛋白(Rabs)的管理下,内体货物回收是亚细胞运输过程的核心,这些蛋白质由上游调节因子协调,并要求下游效应物发挥其功能。在这方面,除了Rab22a,其他几个Rabs已经得到了很好的评价。Rab22a是囊泡运输、早期核内体和再循环核内体形成的关键调节因子。值得注意的是,最近的研究表明Rab22a的免疫学作用与癌症、感染和自身免疫性疾病密切相关。本文综述了Rab22a的调控因子和效应因子。此外,我们还重点介绍了Rab22a在内体货物回收中的作用,包括在以Rab22a为核心的复合体的帮助下回收小管的生物发生,以及不同的内化货物如何在Rab22a、其效应物和调节剂的合作下选择不同的回收路线。值得注意的是,还讨论了与Rab22a对内体货物回收产生影响有关的矛盾和猜测。最后,本文简要介绍了Rab22a影响的各种事件,特别关注与Rab22a征用相关的内体成熟和内体货物循环,以及广泛研究的Rab22a的致癌作用。
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引用次数: 1
Cholangiocytes express an isoform of soluble adenylyl cyclase that is N-linked glycosylated and secreted in extracellular vesicles. 胆管细胞表达一种可溶性腺苷酸环化酶的异构体,该酶被n链糖基化并在细胞外囊泡中分泌。
IF 4.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-09-01 DOI: 10.1111/tra.12904
Simei Go, Hang Lam Li, Jung-Chin Chang, Arthur J Verhoeven, Ronald P J Oude Elferink

Soluble adenylyl cyclase (sAC)-derived cAMP regulates various cellular processes; however, the regulatory landscape mediating sAC protein levels remains underexplored. We consistently observed a 85 kD (sAC85 ) or 75 kD (sAC75 ) sAC protein band under glucose-sufficient or glucose-deprived states, respectively, in H69 cholangiocytes by immunoblotting. Deglycosylation by PNGase-F demonstrated that both sAC75 and sAC85 are N-linked glycosylated proteins with the same polypeptide backbone. Deglycosylation with Endo-H further revealed that sAC75 and sAC85 carry distinct sugar chains. We observed release of N-linked glycosylated sAC (sACEV ) in extracellular vesicles under conditions that support intracellular sAC85 (glucose-sufficient) as opposed to sAC75 (glucose-deprived) conditions. Consistently, disrupting the vesicular machinery affects the maturation of intracellular sAC and inhibits the release of sACEV into extracellular vesicles. The intracellular turnover of sAC85 is extremely short (t1/2 ~30 min) and release of sACEV in the medium was detected within 3 h. Our observations support the maturation and trafficking in cholangiocytes of an N-linked glycosylated sAC isoform that is rapidly released into extracellular vesicles.

可溶性腺苷酸环化酶(sAC)衍生的cAMP调节多种细胞过程;然而,调节sAC蛋白水平的调控景观仍未得到充分探索。通过免疫印迹,我们在H69胆管细胞中分别观察到一个85 kD (sAC85)或75 kD (sAC75)的sAC蛋白带处于葡萄糖充足或葡萄糖缺乏状态。pnase - f去糖基化表明sAC75和sAC85都是具有相同多肽主链的n -链糖基化蛋白。用Endo-H去糖基化进一步揭示sAC75和sAC85携带不同的糖链。我们观察到在支持细胞内sAC85(葡萄糖充足)而不是sAC75(葡萄糖缺乏)条件下,细胞外囊泡中n -连接糖基化sAC (sACEV)的释放。一致地,破坏囊泡机制会影响细胞内sAC的成熟并抑制sACEV向细胞外囊泡的释放。sAC85的胞内转换极短(t1/2 ~ 30min),在3 h内检测到sACEV在培养基中的释放。我们的观察结果支持了一种n链糖基化sAC异构体在胆管细胞中的成熟和运输,这种异构体被迅速释放到细胞外囊泡中。
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引用次数: 2
Deacidification of endolysosomes by neuronal aging drives synapse loss. 神经元老化导致内溶酶体脱酸,导致突触丢失。
IF 4.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-08-01 DOI: 10.1111/tra.12889
Tatiana Burrinha, César Cunha, Michael J Hall, Mafalda Lopes-da-Silva, Miguel C Seabra, Cláudia Guimas Almeida

Previously, we found that age-dependent accumulation of beta-amyloid is not sufficient to cause synaptic decline. Late-endocytic organelles (LEOs) may be driving synaptic decline as lysosomes (Lys) are a target of cellular aging and relevant for synapses. We found that LAMP1-positive LEOs increased in size and number and accumulated near synapses in aged neurons and brains. LEOs' distal accumulation might relate to the increased anterograde movement in aged neurons. Dissecting the LEOs, we found that late-endosomes accumulated while there are fewer terminal Lys in aged neurites, but not in the cell body. The most abundant LEOs were degradative Lys or endolysosomes (ELys), especially in neurites. ELys activity was reduced because of acidification defects, supported by the reduction in v-ATPase subunit V0a1 with aging. Increasing the acidification of aged ELys recovered degradation and reverted synaptic decline, while alkalinization or v-ATPase inhibition, mimicked age-dependent Lys and synapse dysfunction. We identify ELys deacidification as a neuronal mechanism of age-dependent synapse loss. Our findings suggest that future therapeutic strategies to address endolysosomal defects might be able to delay age-related synaptic decline.

先前,我们发现β -淀粉样蛋白的年龄依赖性积累不足以引起突触衰退。由于溶酶体(Lys)是细胞衰老的靶点,与突触相关,晚期内吞细胞器(LEOs)可能会导致突触的衰退。我们发现,在衰老的神经元和大脑中,lamp1阳性的LEOs的大小和数量增加,并在突触附近积聚。LEOs远端积累可能与老龄神经元逆行运动增加有关。通过对LEOs的解剖,我们发现在衰老的神经突中晚期核内体积累,而终末赖氨酸较少,但在细胞体中没有。最丰富的LEOs是降解赖氨酸或内溶酶体(ELys),尤其是在神经突中。随着年龄的增长,v-ATPase亚基V0a1的减少也支持了ELys活性的降低。增加衰老的赖氨酸酸化可以恢复退化和恢复突触衰退,而碱化或v- atp酶抑制则模拟年龄依赖性赖氨酸和突触功能障碍。我们确定ELys脱酸是年龄依赖性突触丧失的神经元机制。我们的研究结果表明,未来解决内溶酶体缺陷的治疗策略可能能够延缓与年龄相关的突触衰退。
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引用次数: 2
Genetic disruption of mammalian endoplasmic reticulum-associated protein degradation: Human phenotypes and animal and cellular disease models. 哺乳动物内质网相关蛋白降解的遗传破坏:人类表型和动物及细胞疾病模型。
IF 4.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-08-01 DOI: 10.1111/tra.12902
Sally Badawi, Feda E Mohamed, Divya Saro Varghese, Bassam R Ali

Endoplasmic reticulum-associated protein degradation (ERAD) is a stringent quality control mechanism through which misfolded, unassembled and some native proteins are targeted for degradation to maintain appropriate cellular and organelle homeostasis. Several in vitro and in vivo ERAD-related studies have provided mechanistic insights into ERAD pathway activation and its consequent events; however, a majority of these have investigated the effect of ERAD substrates and their consequent diseases affecting the degradation process. In this review, we present all reported human single-gene disorders caused by genetic variation in genes that encode ERAD components rather than their substrates. Additionally, after extensive literature survey, we present various genetically manipulated higher cellular and mammalian animal models that lack specific components involved in various stages of the ERAD pathway.

内质网相关蛋白降解(ERAD)是一种严格的质量控制机制,通过这种机制,错误折叠、不组装和一些天然蛋白被降解,以维持适当的细胞和细胞器稳态。一些体外和体内与ERAD相关的研究已经提供了ERAD通路激活及其后续事件的机制见解;然而,其中大多数研究都研究了ERAD底物的影响及其随后影响降解过程的疾病。在这篇综述中,我们介绍了所有报道的人类单基因疾病,这些疾病是由编码ERAD成分的基因而不是其底物的遗传变异引起的。此外,经过广泛的文献调查,我们提出了各种基因操纵的高等细胞和哺乳动物模型,这些模型缺乏参与ERAD途径各个阶段的特定成分。
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引用次数: 0
Syntaxin-5's flexibility in SNARE pairing supports Golgi functions. Syntaxin-5 在 SNARE 配对中的灵活性支持高尔基体的功能。
IF 3.6 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2023-08-01 Epub Date: 2023-06-21 DOI: 10.1111/tra.12903
Zinia D'Souza, Irina Pokrovskaya, Vladimir V Lupashin

Deficiency in the conserved oligomeric Golgi (COG) complex that orchestrates SNARE-mediated tethering/fusion of vesicles that recycle the Golgi's glycosylation machinery results in severe glycosylation defects. Although two major Golgi v-SNAREs, GS28/GOSR1, and GS15/BET1L, are depleted in COG-deficient cells, the complete knockout of GS28 and GS15 only modestly affects Golgi glycosylation, indicating the existence of an adaptation mechanism in Golgi SNARE. Indeed, quantitative mass-spectrometry analysis of STX5-interacting proteins revealed two novel Golgi SNARE complexes-STX5/SNAP29/VAMP7 and STX5/VTI1B/STX8/YKT6. These complexes are present in wild-type cells, but their usage is significantly increased in both GS28- and COG-deficient cells. Upon GS28 deletion, SNAP29 increased its Golgi residency in a STX5-dependent manner. While STX5 depletion and Retro2-induced diversion from the Golgi severely affect protein glycosylation, GS28/SNAP29 and GS28/VTI1B double knockouts alter glycosylation similarly to GS28 KO, indicating that a single STX5-based SNARE complex is sufficient to support Golgi glycosylation. Importantly, co-depletion of three Golgi SNARE complexes in GS28/SNAP29/VTI1B TKO cells resulted in severe glycosylation defects and a reduced capacity for glycosylation enzyme retention at the Golgi. This study demonstrates the remarkable plasticity in SXT5-mediated membrane trafficking, uncovering a novel adaptive response to the failure of canonical intra-Golgi vesicle tethering/fusion machinery.

保守的寡聚高尔基体(COG)复合体能协调SNARE介导的囊泡的系留/融合,这些囊泡能循环利用高尔基体的糖基化机制,缺乏这种复合体会导致严重的糖基化缺陷。虽然COG缺陷细胞中的两个主要高尔基体v-SNARE--GS28/GOSR1和GS15/BET1L被耗尽,但完全敲除GS28和GS15对高尔基体糖基化的影响不大,这表明高尔基体SNARE存在一种适应机制。事实上,对与 STX5 相互作用的蛋白质进行的定量质谱分析发现了两种新型高尔基体 SNARE 复合物--STX5/SNAP29/VAMP7 和 STX5/VTI1B/STX8/YKT6。这些复合物存在于野生型细胞中,但在 GS28 和 COG 缺陷细胞中的使用率显著增加。删除 GS28 后,SNAP29 会以 STX5 依赖性方式增加其高尔基驻留。STX5 缺失和 Retro2- 诱导的高尔基体分流严重影响了蛋白质糖基化,而 GS28/SNAP29 和 GS28/VTI1B 双基因敲除对糖基化的改变与 GS28 KO 相似,这表明基于 STX5 的单一 SNARE 复合物足以支持高尔基体糖基化。重要的是,在 GS28/SNAP29/VTI1B TKO 细胞中同时缺失三种高尔基体 SNARE 复合物会导致严重的糖基化缺陷,并降低糖基化酶在高尔基体的保留能力。这项研究证明了 SXT5 介导的膜贩运具有显著的可塑性,揭示了对高尔基体内典型囊泡系留/融合机制失效的一种新的适应性反应。
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引用次数: 0
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