更新于：2024-05-01

RAB27A

RAB27A, member RAS oncogene family

更新于：2024-05-01

基本信息

别名

GS2、GTP-binding protein Ram、HsT18676

+ [6]

简介

Small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate homeostasis of late endocytic pathway, including endosomal positioning, maturation and secretion (PubMed:30771381). Plays a role in cytotoxic granule exocytosis in lymphocytes. Required for both granule maturation and granule docking and priming at the immunologic synapse.

关联

100 项与 RAB27A 相关的临床结果

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100 项与 RAB27A 相关的转化医学

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0 项与 RAB27A 相关的专利（医药）

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项与 RAB27A 相关的文献（医药）

2024-02-09·Parasites & vectors

The role of Rab27 in tick extracellular vesicle biogenesis and pathogen infection.

Article

作者: L Rainer Butler ; Nisha Singh ; Liron Marnin ; Luisa M Valencia ; Anya J O'Neal ; Francy E Cabrera Paz ; Dana K Shaw ; Adela S Oliva Chavez ; Joao H F Pedra

BACKGROUND:

The blacklegged tick, Ixodes scapularis, transmits most vector-borne diseases in the US. It vectors seven pathogens of public health relevance, including the emerging human pathogen Anaplasma phagocytophilum. Nevertheless, it remains critically understudied compared to other arthropod vectors. Ixodes scapularis releases a variety of molecules that assist in the modulation of host responses. Recently, it was found that extracellular vesicles (EVs) carry several of these molecules and may impact microbial transmission to the mammalian host. EV biogenesis has been studied in mammalian systems and is relatively well understood, but the molecular players important for the formation and secretion of EVs in arthropods of public health relevance remain elusive. RabGTPases are among the major molecular players in mammalian EV biogenesis. They influence membrane identity and vesicle budding, uncoating, and motility.

METHODS:

Using BLAST, an in silico pathway for EV biogenesis in ticks was re-constructed. We identified Rab27 for further study. EVs were collected from ISE6 tick cells after knocking down rab27 to examine its role in tick EV biogenesis. Ixodes scapularis nymphs were injected with small interfering RNAs to knock down rab27 and then fed on naïve and A. phagocytophilum-infected mice to explore the importance of rab27 in tick feeding and bacterial acquisition.

RESULTS:

Our BLAST analysis identified several of the proteins involved in EV biogenesis in ticks, including Rab27. We show that silencing rab27 in I. scapularis impacts tick fitness. Additionally, ticks acquire less A. phagocytophilum after rab27 silencing. Experiments in the tick ISE6 cell line show that silencing of rab27 causes a distinct range profile of tick EVs, indicating that Rab27 is needed to regulate EV biogenesis.

CONCLUSIONS:

Rab27 is needed for successful tick feeding and may be important for acquiring A. phagocytophilum during a blood meal. Additionally, silencing rab27 in tick cells results in a shift of extracellular vesicle size. Overall, we have observed that Rab27 plays a key role in tick EV biogenesis and the tripartite interactions among the vector, the mammalian host, and a microbe it encounters.

2024-02-09·Current microbiology

Forskolin Enhances Antitumor Effect of Oncolytic Measles Virus by Promoting Rab27a Dependent Vesicular Transport System.

Article

作者: Mao Xia ; Yangbin Wang ; Yongquan Xia ; Jiawei Zeng

The measles vaccine virus strain (MV-Edm) serves as a potential platform for the development of effective oncolytic vectors. Nevertheless, despite promising pre-clinical data, our comprehension of the factors influencing the efficacy of MV-Edm infection and intratumoral spread, as well as the interactions between oncolytic viruses and specific chemotherapeutics associated with viral infection, remains limited. Therefore, we investigated the potency of Forskolin in enhancing the antitumor effect of oncolytic MV-Edm by promoting the Rab27a-dependent vesicular transport system. After infecting cells with MV-Edm, we observed an increased accumulation of cytoplasmic vesicles. Our study demonstrated that MV-Edm infection and spread in tumors, which are indispensable processes for viral oncolysis, depend on the vesicular transport system of tumor cells. Although tumor cells displayed a responsive mechanism to restrain the MV-Edm spread by down-regulating the expression of Rab27a, a key member of the vesicle transport system, over-expression of Rab27a promoted the oncolytic efficacy of MV-Edm towards A549 tumor cells. Additionally, we found that Forskolin, a Rab27a agonist, was capable of promoting the oncolytic effect of MV-Edm in vitro. Our study revealed that the vesicle transporter Rab27a could facilitate the secretion of MV-Edm and the generation of syncytial bodies in MV-Edm infected cells during the MV-Edm-mediated oncolysis pathway. The results of the study demonstrate that a combination of Forskolin and MV-Edm exerts a synergistic anti-tumor effect in vitro, leading to elevated oncolysis. This finding holds promise for the clinical treatment of patients with tumors.

2024-02-07·Journal of orthopaedic surgery and research

circ_0029463 promotes osteoclast differentiation by mediating miR-134-5p/Rab27a axis.

Article

作者: Lian Tang ; Lin Yuan ; Jiyuan Yan ; Jianhua Ge ; Zhi Lian ; Zhong Li

OBJECTIVE:

Osteoporosis is the imbalance in bone homeostasis between osteoblasts and osteoclasts. In this study, we investigated the effects of the circ_0029463/miR-134-5p/Rab27a axis on RANKL-induced osteoclast differentiation.

METHODS:

RT-qPCR and western blotting were used to detect the expression of circ_0029463, miR-134-5p, and Rab27a in tissues from patients with osteoporosis and in RANKL-induced osteoclasts. Osteoclast differentiation was verified by TRAP staining. Osteoclast biomarkers, including NFATc1, TRAP, and CTSK, were measured. The target and regulatory relationships between circ_0029463, miR-134-5p, and the Rab27a axis were verified using RIP, dual-luciferase reporter gene, and RNA pull-down assays.

RESULTS:

Elevated expression of circ_0029463 and Rab27a and decreased miR-134-5p expression were observed in the tissues of patients with osteoporosis, and a similar expression pattern was observed in RANKL-induced osteoclasts. Suppression of circ_0029463 expression or miR-134-5p overexpression curbed RANKL-induced osteoclast differentiation, whereas such an effect was abolished by Rab27 overexpression. circ_0029463 sponges miR-134-5p to induce Rab27a expression.

CONCLUSION:

circ_0029463 sponges miR-134-5p to abolish its suppressive effect of miR-134-5p on Rab27a expression, thereby promoting osteoclast differentiation.

项与 RAB27A 相关的新闻（医药）

2023-09-16

·生物探索

非酒精性脂肪肝影响心血管疾病发生和进展的潜在机理

非酒精性脂肪性肝病(NAFLD)目前是一种日益增长的慢性流行病，并与心血管疾病(CVD)相关。然而，NAFLD如何影响CVD的发生和进展仍然不清楚。2023年9月4日，中山大学凌文华及广州医科大学Xue Hongliang共同通讯在Journal of Hepatology（IF=26）在线发表题为“Hepatic steatosis aggravates atherosclerosis via small extracellular vesicle-mediated inhibition of cellular cholesterol efflux”的研究论文，该研究表明肝脂肪变性通过小细胞外囊泡介导的抑制细胞胆固醇外排加重动脉粥样硬化。来自脂肪变性肝细胞的sEVs通过抑制ABCA在动脉粥样硬化进展中的作用。此外，肝细胞特异性缺失Rab27a可显著改善ApoE-/-小鼠高脂高胆固醇(HFHC)诱导的AS进展。Rab27a是调节sEVs释放的关键GTPase。miRNA深度测序结果显示，脂肪变性肝细胞的sEVs中富集了miR-30a-3p。miR-30a-3p直接靶向ABCA1 3'UTR抑制ABCA1表达和胆固醇外排。anagomiR-30a-3p治疗显著减轻HFHC喂养的ApoE-/-小鼠的动脉粥样硬化进展。此外，NAFLD患者血清sEVs降低了泡沫细胞中的胆固醇外排水平。sEV-miRNA-30a-3p相对含量与泡沫细胞胆固醇外排水平变化呈负相关。总之，脂肪变性肝细胞衍生的sEVs通过miR-30a-3p/ABCA1轴促进泡沫细胞形成和动脉粥样硬化。靶向和减少肝脏脂肪变性sEVs分泌或miR-30a-3p可能是减缓NAFLD驱动的AS进展的潜在治疗方法。久坐不动的生活方式和高热量食物的过度消费导致非酒精性脂肪性肝病(NAFLD)成为全球最普遍的肝病。有证据表明，NAFLD可影响包括心血管疾病(CVDs)在内的主要肝外代谢。肝脂肪变性与CVD和CVD相关事件的风险密切相关。动脉粥样硬化(AS)的发展和进展是心血管疾病的病理生理基础。然而，肝脂肪变性加速AS发展和进展的确切机制尚不清楚。细胞外囊泡(Extracellular vesicles，简称EVs)是源自供体细胞的膜状颗粒，可将其载货蛋白或miRNA运送到受体细胞，在代谢信号的器官间传递中发挥重要作用。作为细胞内通信的载体，EVs载货量可随着供体细胞受到的刺激而改变。小EVs通常指直径小于200 nm的EVs，其中包括外泌体和微泡。脂质超载后，肝细胞来源的sEVs在释放sEVs的数量和组成方面显示出巨大的变化。来自脂肪变性肝细胞的小EVs可加重肝脏炎症和NAFLD进展。然而，来自脂肪性肝细胞的sEVs是否会影响肝外代谢状况，尤其是AS，以及来自肝脂肪变性的细胞特异性信号如何调节AS进展仍然是悬而未决的问题。机理模式图（图源自Journal of Hepatology）动脉内膜中富含胆固醇的泡沫细胞是动脉粥样硬化进展的标志。动脉粥样硬化中泡沫细胞的主要细胞类型是巨噬细胞，巨噬细胞可以通过逆向胆固醇转运降低过量的细胞胆固醇水平 (RCT)。RCT的第一步是HDL通过ABCA1、ABCG1或SR-BI转运蛋白促进巨噬细胞的胆固醇外排，然后HDL-胆固醇被转运到肝脏排泄。越来越多的证据表明，巨噬细胞的RCT损伤会加剧AS的进展。该研究从脂肪变性肝细胞中分离了sEVs，并分析了这些sEVs在泡沫细胞形成和AS进展中的作用。研究结果表明，脂肪变性肝细胞来源的sEVs通过miR-30a-3p/ABCA1途径抑制巨噬细胞RCT，从而加剧泡沫细胞的形成和AS的进展，这表明抑制脂肪变性肝细胞的sEVs分泌或靶向miR-30a-3p可能能够改善NAFLD驱动的AS。此外，该研究肝脂肪变性在AS进展中的因果作用提供了概念验证的实验证据。总之，该研究揭示了肝脂肪变性通过sEVs在AS进展中的因果作用。来自脂肪变性肝细胞的sEVs可通过miR-30a-3p/ABCA1轴促进泡沫细胞形成。靶向和抑制sEVs分泌或miR-30a-3p可能是减轻NAFLD驱动的AS发展和进展的新治疗方法。文章来源“iNture”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

临床研究临床结果

2023-07-25

·生物谷

专访中山大学彭晖｜发现腹膜纤维化产生新机制，设计AAV1基因疗法成功治疗小鼠模型

近日，中山大学附属第三医院彭晖教授团队通过对腹膜的单细胞转录组分析和细胞外囊泡的蛋白质组学分析，发现了导致腹膜纤维化的全新作用机制，为开发腹膜纤维化治疗策略提供了新思路。目前，这项研究已经以“Extr 发现腹膜纤维化潜在分子靶点并设计基因疗法成功治疗小鼠 “长期的腹膜透析容易导致腹膜纤维化，进而引起患者超滤功能障碍，甚至逐渐进展为超滤衰竭，为此，我们想探讨腹膜透析相关腹膜纤维化发生发展的机制，以找寻相关的治疗靶点。”彭晖介绍道。既往研究已经证实，腹膜细胞间的交流能够调控腹膜纤维化的发生。“作为细胞间交流的通讯介质，细胞外囊泡是当今的研究热点，其可以通过传递 DNA、RNA、蛋白质、脂质等生物活性分子调节靶细胞的生物学行为。所以，我们聚焦于细胞外囊泡在腹膜纤维化中的作用开展此次研究工作。”她说道。采用 AVV1 载体基因治疗腹膜纤维化未来有重要临床转化价值

基因疗法

2023-07-09

·生物谷

《细胞·代谢》：脂肪肝促进肠癌肝转移的机制，找到了！

该研究验证了脂肪肝中由肝细胞衍生的EVs在结直肠癌肝转移过程中的重要作用，并进一步揭示了其具体分子机制，为日后结直肠癌肝转移的治疗提供了新的思路。脂肪肝患者更易发生结直肠癌肝转移的机制找到了！近期，美国西达赛奈医学中心的Ekihiro Seki研究团队发表了一项研究，发现脂肪肝不仅会对肝脏本身产生影响，还能通过释放细胞外囊泡（EVs）创造一种有利于结直肠癌转移的肝脏微环境。机制上，脂肪肝会上调Rab27a表达，增加肝脏细胞产生EVs，这些EVs将含有调节YAP信号通路的微小RNA（miRNA）转移到癌细胞中，通过抑制LATS2基因的表达来激活YAP信号通路。YAP信号通路的激活促进了M2巨噬细胞的浸润和CYR61的产生，形成了一个免疫抑制的微环境，进一步加速了结直肠癌的肝转移。研究发表在《细胞·代谢》上，华中科技大学同济医学院的汪志军及涂炜也是本文的共同第一作者[1]。论文首页截图结直肠癌是最常见的恶性肿瘤之一，也是癌症相关死亡的第二大原因。肝脏是结直肠癌最常见的转移部位，约有70%的结直肠癌患者都会发生肝转移。肥胖和非酒精性脂肪肝病（NAFLD）是结直肠癌的重要危险因素。近年来有不少研究显示，脂肪肝增加了结直肠癌肝转移的发生风险，影响患者预后，但其背后的分子机制还不是很清楚。为了进一步探究脂肪肝促进结直肠癌肝转移的机制，研究人员建立了有或没有脂肪肝的结直肠癌肝转移小鼠模型（野生[wt]小鼠喂食高脂饮食[HFD]和低脂饮食[LFD]6周，脾脏注射MC38结直肠癌细胞2周）。结果发现，HFD增加了转移性肿瘤的数量和大小，同时，小鼠血清中的EVs数量也变多了。鉴于EVs能促进癌症生长，研究人员用HFD小鼠血清中的EVs处理MC38细胞，结果发现癌细胞的增殖、迁移和侵袭能力的确变强了。 EVs促进结直肠癌肝转移在人体中，研究人员同样观察到NAFLD患者血清中EVs的数量比健康人多的多。更重要的是，NAFLD患者血清中EVs也可以促进HCT116细胞的生长、迁移和侵袭。由于血清中的EVs也包含肝脏来源的EVs，而脂肪肝又可以产生EVs，因此研究人员猜想脂肪肝产生的EVs是促进转移性肿瘤生长的关键。为了验证这一猜想，研究人员在原代肝细胞和Huh7细胞系中加入了棕榈酸（PA），在PA刺激下，肝细胞产生了更多的EVs。这些EVs可被结直肠癌细胞（MC38和HCT116细胞）吸收。吸收EVs后，结直肠癌细胞的侵袭性变强了。总之，以上结果提示，脂肪肝来源的EVs会加速肝脏转移性肿瘤的生长。正常情况下，EVs产生受中性鞘磷脂酶和Rab27a/b蛋白调控，在HFD小鼠、PA处理过的肝细胞以及NAFLD患者肝细胞中，研究人员均观察到Rab27a表达上调。当Rab27a被敲降后，EVs产生减少，HFD小鼠肝脏转移性肿瘤生长被抑制了，相反，Rab27a过表达则会促进结直肠癌的肝转移。因此研究人员认为，脂肪肝促进结直肠癌肝转移是通过上调Rab27a表达，增加EVs的产生实现的。 Rab27a表达对转移性肿瘤大小的影响接下来，研究人员分析了EVs的组成，通过miRNA PCR定量分析发现，miR-103、miR-25和miR-92a这三种miRNA在肝脏来源的EVs中表达特别丰富。当研究人员用这三个miRNA处理MC38和HCT116细胞后，这些癌细胞的增殖、迁移和侵袭能力都会增加。随后，研究人员又寻找了这三个miRNA的直接靶标，利用多种目标基因预测算法，研究人员发现了与这三个miRNA有关的抑癌基因，LATS2。LATS2也是促癌YAP信号的负调控因子，当用这三个miRNAs处理结直肠癌细胞时，LATS2的表达明显降低，而YAP蛋白的表达则明显增加。这一现象在HFD小鼠模型中也得到了证实。 LATS2表达下调此外，研究人员还发现，敲降Rab27a后，可逆转由于HFD引起的LATS2表达的下降和YAP及YAP靶基因（Ankrd1、Axl1、Ccn2和Ccn1）表达的增加。这些结果表明，EVs可通过抑制LATS2基因的表达来激活YAP这一促癌信号通路。那YAP信号通路的激活会对结直肠癌的肝转移产生哪些影响呢？在体外实验中，研究人员发现，YAP信号通路的激活会募集更多的M2型肿瘤相关巨噬细胞，形成了一个免疫抑制的微环境。若敲降Yap1，HFD和LFD小鼠的转移性肿瘤生长都受到了抑制，此外，敲降Yap1也减少了M2型肿瘤相关巨噬细胞的聚集。既往研究显示，YAP的一个靶基因，Ccn1，编码的一种蛋白CYR61，会促进肿瘤增长。当研究人员沉默Ccn1后，发现脂肪肝中M2型肿瘤相关巨噬细胞的浸润和基因表达都受到了抑制。以上结果表明，YAP信号通路的激活会促进M2巨噬细胞的浸润和CYR61的产生，进一步促进了肿瘤的增长。研究机制图最后，研究人员在人类伴有脂肪肝的结直肠癌肝转移患者中也观察到类似机制。总之，该研究验证了脂肪肝中由肝细胞衍生的EVs在结直肠癌肝转移过程中的重要作用，并进一步揭示了其具体分子机制，为日后结直肠癌肝转移的治疗提供了新的思路。参考文献： [1]Wang Z, Kim SY, Tu W, Kim J, Xu A, Yang YM, Matsuda M, Reolizo L, Tsuchiya T, Billet S, Gangi A, Noureddin M, Falk BA, Kim S, Fan W, Tighiouart M, You S, Lewis MS, Pandol SJ, Di Vizio D, Merchant A, Posadas EM, Bhowmick NA, Lu SC, Seki E. Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment. Cell Metab. 2023 May 9:S1550-4131(23)00140-7. doi: 10.1016/j.cmet.2023.04.013.