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更新于：2025-01-23

RAB10

更新于：2025-01-23

基本信息

别名

RAB10、RAB10, member RAS oncogene family、Ras-related protein Rab-10

简介

The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes (PubMed:21248164). Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:21248164). That Rab is mainly involved in the biosynthetic transport of proteins from the Golgi to the plasma membrane (PubMed:21248164). Regulates, for instance, SLC2A4/GLUT4 glucose transporter-enriched vesicles delivery to the plasma membrane (By similarity). In parallel, it regulates the transport of TLR4, a toll-like receptor to the plasma membrane and therefore may be important for innate immune response (By similarity). Also plays a specific role in asymmetric protein transport to the plasma membrane (PubMed:16641372). In neurons, it is involved in axonogenesis through regulation of vesicular membrane trafficking toward the axonal plasma membrane (By similarity). In epithelial cells, it regulates transport from the Golgi to the basolateral membrane (PubMed:16641372). May play a role in the basolateral recycling pathway and in phagosome maturation (By similarity). May play a role in endoplasmic reticulum dynamics and morphology controlling tubulation along microtubules and tubules fusion (PubMed:23263280). Together with LRRK2, RAB8A, and RILPL1, it regulates ciliogenesis (PubMed:30398148). When phosphorylated by LRRK2 on Thr-73, binds RILPL1 and inhibits ciliogenesis (PubMed:30398148). (Microbial infection) Upon Legionella pneumophila infection promotes endoplasmic reticulum recruitment and bacterial replication. Plays a role in remodeling the Legionella-containing vacuole (LCV) into an endoplasmic reticulum-like vacuole.

关联

100 项与 RAB10 相关的临床结果

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100 项与 RAB10 相关的转化医学

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0 项与 RAB10 相关的专利（医药）

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400

项与 RAB10 相关的文献（医药）

2024-12-01·Cell Reports

Legionella uses host Rab GTPases and BAP31 to create a unique ER niche

Article

作者: Tagaya, Mitsuo ; Yanai, Yu ; Inoue, Hiroki ; Oide, Hiromu ; Mukherjee, Shaeri ; Chadha, Attinder ; Paul, Manish ; Arasaki, Kohei ; Saha, Saradindu ; Wakana, Yuichi

The bacterium Legionella pneumophila secretes numerous effector proteins that manipulate endoplasmic reticulum (ER)-derived vesicles to form the Legionella-containing vacuole (LCV). Despite extensive studies, whether the LCV membrane is separate from or connected to the host ER network remains unclear. Here, we show that the smooth ER (sER) is closely associated with the LCV early in infection. Remarkably, Legionella forms a distinct rough ER (rER) niche at later stages, disconnected from the host ER network. We discover that host small GTPases Rab10 and Rab4 and an ER protein, BAP31, play crucial roles in transitioning the LCV from an sER to an rER. Additionally, we have identified a Legionella effector, Lpg1152, that binds to BAP31. Interestingly, the optimal growth of Legionella is dependent on both BAP31 and Lpg1152. These findings detail the complex interplay between host and pathogen in transforming the LCV membrane from a host-associated sER to a distinct rER.

2024-11-20·Human Molecular Genetics

14-3-3 phosphorylation inhibits 14-3-3θ’s ability to regulate LRRK2 kinase activity and toxicity

Article

作者: Ekkatine, Roschongporn ; Pattanayak, Rudradip ; Petit, Chad M ; Yacoubian, Talene A

AbstractLRRK2 mutations are among the most common genetic causes for Parkinson’s disease (PD), and toxicity is associated with increased kinase activity. 14-3-3 proteins are key interactors that regulate LRRK2 kinase activity. Phosphorylation of the 14-3-3θ isoform at S232 is dramatically increased in human PD brains. Here we investigate the impact of 14-3-3θ phosphorylation on its ability to regulate LRRK2 kinase activity. Both wildtype and the non-phosphorylatable S232A 14-3-3θ mutant reduced the kinase activity of wildtype and G2019S LRRK2, whereas the phosphomimetic S232D 14-3-3θ mutant had minimal effects on LRRK2 kinase activity, as determined by measuring autophosphorylation at S1292 and T1503 and Rab10 phosphorylation. However, wildtype and both 14-3-3θ mutants similarly reduced the kinase activity of the R1441G LRRK2 mutant. 14-3-3θ phosphorylation did not promote global dissociation with LRRK2, as determined by co-immunoprecipitation and proximal ligation assays. 14-3-3s interact with LRRK2 at several phosphorylated serine/threonine sites, including T2524 in the C-terminal helix, which can fold back to regulate the kinase domain. Interaction between 14-3-3θ and phosphorylated T2524 LRRK2 was important for 14-3-3θ’s ability to regulate kinase activity, as wildtype and S232A 14-3-3θ failed to reduce the kinase activity of G2019S/T2524A LRRK2. Finally, we found that the S232D mutation failed to protect against G2019S LRRK2-induced neurite shortening in primary cultures, while the S232A mutation was protective. We conclude that 14-3-3θ phosphorylation destabilizes the interaction of 14-3-3θ with LRRK2 at T2524, which consequently promotes LRRK2 kinase activity and toxicity.

2024-11-01·Developmental Dynamics

Proteomic profiling of TBC1 domain family member 21‐null sperms reveals the critical roles of TEKT 1 in their tail defects

Article

作者: Huang, Chia‐Yen ; Wang, Ya‐Yun ; Ke, Chih‐Chun ; Chan, Chying‐Chyuan ; Pan, Pei‐Yi ; Ku, Wei‐Chi ; Au, Chin‐Fong ; Lin, Yu‐Hua ; Lin, Ying‐Hung

AbstractBackgroundApproximately 7% of the males exhibit reduced fertility; however, the regulatory genes and pathways involved remain largely unknown. TBC1 domain family member 21 (TBC1D21) contains a conserved RabGAP catalytic domain that induces GDP/GTP exchange to inactivate Rabs by interacting with microtubules. We previously reported that Tbc1d21‐null mice exhibit severe sperm tail defects with a disrupted axoneme, and that TBC1D21 interacts with RAB10. However, the pathological mechanisms underlying the Tbc1d21 loss‐induced sperm tail defects remain unknown.ResultsMurine sperm from wild‐type and Tbc1d21‐null mice were comparatively analyzed using proteomic assays. Over 1600 proteins were identified, of which 15 were significantly up‐regulated in Tbc1d21‐null sperm. Notably, several tektin (TEKT) family proteins, belonging to a type of intermediate filament critical for stabilizing the microtubular structure of cilia and flagella, were significantly up‐regulated in Tbc1d21−/− sperm. We also found that TBC1D21 interacts with TEKT1. In addition, TEKT1 co‐localized with RAB10 during sperm tail formation. Finally, we found Tbc1d21‐null sperm exhibited abnormal accumulation of TEKT1 in the midpiece region, accompanied by disrupted axonemal structures.ConclusionsThese results reveal that TBC1D21 modulates TEKTs protein localization in the axonemal transport system during sperm tail formation.

项与 RAB10 相关的新闻（医药）

2024-10-08

·PipelineReview

Halia Therapeutics Announces First Healthy Volunteer Dosed with HT-4253, a Novel Oral LRRK2 Inhibitor Targeting Neuroinflammation in Alzheimer's Disease

LEHI, Utah I October 7, 2024 I Halia Therapeutics, a clinical-stage biopharmaceutical company at the forefront of developing innovative treatments for inflammatory and neurodegenerative diseases, today announced that the first healthy volunteer was dosed in its Phase 1 clinical trial evaluating its LRRK2 inhibitor, HT-4253, for a potential treatment for Alzheimer’s Disease. “Dosing the first subject in the Phase 1 trial of HT-4253 marks a significant step in the fight against neurodegenerative diseases such as Alzheimer’s disease,” said Dr. David Bearss , CEO of Halia Therapeutics. “We believe that HT-4253 will provide a groundbreaking treatment option for patients who currently have few choices to prevent or delay Alzheimer’s onset, as the drug targets the underlying neuroinflammation linked to causing neurocognitive disease.” The Phase 1 clinical trial ( ClinicalTrials.gov ID: NCT06537817 ) is a first-in-human, randomized, placebo-controlled, double-blind study evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HT-4253. This study will employ a single ascending dose (SAD) and multiple ascending dose (MAD) format, designed to explore the potential of HT-4253 to inhibit LRRK2—a critical enzyme designed to explore the potential of HT-4253 to inhibit LRRK2. Recent human genetic studies have revealed specific variants of the Rab10 gene protect individuals with the APOE4 genotype—a known risk factor for Alzheimer’s disease. These variants inhibit Rab10, a key protein activated by LRRK2, thus reducing neuroinflammation and offering neuroprotection. Halia’s LRRK2 inhibitor, HT-4253, mimics these Rab10 variants by blocking LRRK2, which in turn prevents Rab10 activation. This mechanism shows promise for preventing or delaying Alzheimer’s onset in APOE4 carriers by replicating the protective effects observed in resilient individuals. About HT-4253 HT-4253 is an orally administered small molecule tablet with excellent brain penetration. It targets LRRK2, a key mediator of neuroinflammation. Chronic brain inflammation drives several neurodegenerative diseases, including Parkinson’s and Alzheimer’s. Halia scientists have demonstrated that LRRK2 is crucial in regulating neuroinflammation. By inhibiting LRRK2, HT-4253 could offer a novel approach to treating neurodegenerative diseases with an inflammatory component, potentially altering disease progression. About Halia Therapeutics, Inc. Halia Therapeutics is pioneering novel therapeutics to enhance patients’ lives affected by chronic inflammatory disorders and neurodegenerative diseases. Our initial programs focus on NEK7 and LRRK2 targets. Our lead candidate, HT-6184—a novel NEK7/NLRP3 inhibitor—has successfully completed a Phase I study ( NCT05447546 ). This study evaluated HT-6184’s safety and tolerability when administered as single or multiple oral doses at escalating levels in healthy volunteers. Additionally, we’ve completed a Phase II trial assessing HT-6184’s efficacy on post-procedure diagnostic biomarkers of inflammation and pain ( NCT06241742 ). Currently, we’re conducting a Phase II trial to investigate HT-6184’s efficacy in treating lower-risk myelodysplastic syndromes (LR-MDS). Headquartered in Lehi, Utah, Halia Therapeutics is at the forefront of innovative drug development. For more information, visit www.haliatx.com or follow us on LinkedIn and Twitter (X) . SOURCE: Halia Therapeutics

临床1期临床2期

2024-10-07

·BioSpace

Halia Therapeutics Announces First Healthy Volunteer Dosed with HT-4253, a Novel Oral LRRK2 Inhibitor Targeting Neuroinflammation in Alzheimer’s Disease

LEHI, Utah , Oct. 7, 2024 /PRNewswire/ -- Halia Therapeutics, a clinical-stage biopharmaceutical company at the forefront of developing innovative treatments for inflammatory and neurodegenerative diseases, today announced that the first healthy volunteer was dosed in its Phase 1 clinical trial evaluating its LRRK2 inhibitor, HT-4253, for a potential treatment for Alzheimer’s Disease. “Dosing the first subject in the Phase 1 trial of HT-4253 marks a significant step in the fight against neurodegenerative diseases such as Alzheimer’s disease,” said Dr. David Bearss , CEO of Halia Therapeutics. “We believe that HT-4253 will provide a groundbreaking treatment option for patients who currently have few choices to prevent or delay Alzheimer’s onset, as the drug targets the underlying neuroinflammation linked to causing neurocognitive disease.” The Phase 1 clinical trial ( ClinicalTrials.gov ID: NCT06537817 ) is a first-in-human, randomized, placebo-controlled, double-blind study evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HT-4253. This study will employ a single ascending dose (SAD) and multiple ascending dose (MAD) format, designed to explore the potential of HT-4253 to inhibit LRRK2—a critical enzyme designed to explore the potential of HT-4253 to inhibit LRRK2. Recent human genetic studies have revealed specific variants of the Rab10 gene protect individuals with the APOE4 genotype—a known risk factor for Alzheimer’s disease. These variants inhibit Rab10, a key protein activated by LRRK2, thus reducing neuroinflammation and offering neuroprotection. Halia’s LRRK2 inhibitor, HT-4253, mimics these Rab10 variants by blocking LRRK2, which in turn prevents Rab10 activation. This mechanism shows promise for preventing or delaying Alzheimer’s onset in APOE4 carriers by replicating the protective effects observed in resilient individuals. About HT-4253 HT-4253 is an orally administered small molecule tablet with excellent brain penetration. It targets LRRK2, a key mediator of neuroinflammation. Chronic brain inflammation drives several neurodegenerative diseases, including Parkinson’s and Alzheimer’s. Halia scientists have demonstrated that LRRK2 is crucial in regulating neuroinflammation. By inhibiting LRRK2, HT-4253 could offer a novel approach to treating neurodegenerative diseases with an inflammatory component, potentially altering disease progression. About Halia Therapeutics, Inc. Halia Therapeutics is pioneering novel therapeutics to enhance patients’ lives affected by chronic inflammatory disorders and neurodegenerative diseases. Our initial programs focus on NEK7 and LRRK2 targets. Our lead candidate, HT-6184—a novel NEK7/NLRP3 inhibitor—has successfully completed a Phase I study ( NCT05447546 ). This study evaluated HT-6184’s safety and tolerability when administered as single or multiple oral doses at escalating levels in healthy volunteers. Additionally, we’ve completed a Phase II trial assessing HT-6184’s efficacy on post-procedure diagnostic biomarkers of inflammation and pain ( NCT06241742 ). Currently, we’re conducting a Phase II trial to investigate HT-6184’s efficacy in treating lower-risk myelodysplastic syndromes (LR-MDS). Headquartered in Lehi, Utah , Halia Therapeutics is at the forefront of innovative drug development. For more information, visit or follow us on LinkedIn and Twitter (X) . Company Contact Halia Therapeutics info@haliatx.com +1 (385) 355-4315 Media Contact: Ignacio Guerrero-Ros , Ph.D. Russo Partners, LLC Ignacio.Guerrero-Ros@russopartnersllc.com \ +1 (646) 942-5604 View original content to download multimedia: SOURCE Halia Therapeutics

临床1期临床2期

2024-08-08

·生物谷

PNAS｜北京大学、北京协和医院等团队联合揭示微量样本蛋白质组学定量分析揭示迁移体囊泡转运机制

7月17日，北京大学陈扬副研究员和现任北京协和医院疑难重症罕见病国家重点实验室执行副主任的黄超兰教授（Catherine C.L. Wong）为共同通讯在PNAS上发表论文“Rab10-CAV1 mediated intraluminal vesicle transport to migrasomes”。该研究通过免疫标记、电镜、蛋白质组学、基因敲除/突变/敲减/激活、动物实验等多种实验和分析手段，严密的证实了Rab10-CAV1定位于迁移体的腔内小囊泡。Rab10-CAV1的转运需要Myosin Va和RILPL2协同，并且该过程受激酶LRRK2对Rab10磷酸化的调控。CSF-1通过该调控机制转运到迁移体，并促进单核细胞向巨噬细胞分化。迁移体是一种新型细胞器。它是细胞迁移过程中，在收缩纤维的末端或交叉点形成的直径为微米级的囊泡结构。迁移体一个重要特征是内部含有的许多纳米级的囊泡结构（图1），携带多种生物活性物质，介导了细胞迁移和细胞间通讯等生物学过程。根据细胞环境的变化，迁移体内携带的物质会产生巨大差异。因此，迁移体囊泡形成机制对诸多生理病理过程的阐释至关重要。图1.小鼠成纤维细胞 L929迁移体透射电镜(TEM)图像 Rab家族蛋白（由大约70个成员组成），在细胞内囊泡运输的各个步骤起着关键作用。该研究首先用GFP标记、WB等方法，探索Rab蛋白在细胞中的定位。结果表明，Rab8, Rab10, Rab17, Rab36和Rab29定位迁移体内部，而其他Rab GTP酶则定位于表面。尤其是Rab10，在迁移体中显示出强烈的点状定位，表明它可能定位于迁移体的纳米级小囊泡中。为了进一步分析Rab10蛋白在迁移体囊泡形成机制中的功能，研究者采用无标记定量的蛋白质组学方法，对特异性表达Rab10 Q68L（Rab GTP结合形式，定位于收缩纤维和迁移体中）和Rab10 T23N（Rab GDP结合形式，定位于细胞质中）的小鼠成纤维细胞L929的迁移体进行相对定量分析。结果表明，差异蛋白主要与囊泡的组织结构、运输和对接相关的通路有关（图2左），Rab10蛋白在Rab10 Q68L迁移体中显著上调表达（图2右）。且多种CAV蛋白也显著上调表达（图2右），它们对膜微囊的形成至关重要。进一步电镜观察发现，CAV1定位于迁移体内部的纳米级囊泡中。Rab10与CAV1共定位于迁移体囊泡中，是迁移体腔内囊泡的重要组分。图2. Rab10 Q68L和Rab10 T23N小鼠成纤维细胞 L929迁移体蛋白质组学分析蛋白质组学分析结果同时提示，细胞骨架蛋白和多种肌动蛋白、微管相关马达蛋白，以及衔接蛋白在Rab10 Q68L的L929细胞的迁移体中显著富集。对其中重点关注的马达蛋白和衔接蛋白在细胞中做基因敲除实验后发现，在所有敲除细胞中都检测到了Rab10与CAV1的表达，但敲除Myosin Va和RILPL2显著清除了Rab10与CAV1的共定位。过表达这两个基因可以使这一现象恢复。进一步免疫荧光分析显示，Myosin Va、RILPL2和Rab10、CAV1共定位于迁移体中。这两种蛋白在迁移体腔内囊泡转运机制中同样发挥着重要的功能。研究者进一步用GFP标记方法观察到，磷酸化修饰的Rab10与CAV1共定位于迁移体中。进一步的Rab点突变实验证实，Rab10-CAV1从囊泡到迁移体的转运过程受Rab10磷酸化的调控。以往的研究提示，LRRK2可使Rab10的苏氨酸73（T73）磷酸化。在L929细胞敲低LRRK2的表达显著降低了T73磷酸化，同时抑制了Rab10-CAV1的转运。LRRK2激活实验则显示出相反的磷酸化效应。这表明LRRK2介导的Rab10磷酸化对于Rab10-CAV1囊泡转运到迁移小体这一过程至关重要。研究者还进一步通过细胞和小鼠实验证实，由成纤维细胞分泌的CSF-1位于迁移体膜内，且促进了单核细胞向巨噬细胞的分化。

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