更新于：2024-05-01

RB1CC1

RB1 inducible coiled-coil 1

更新于：2024-05-01

基本信息

别名

ATG17、Cc1、DRAGOU14

+ [8]

简介

Involved in autophagy (PubMed:21775823). Regulates early events but also late events of autophagosome formation through direct interaction with Atg16L1 (PubMed:23392225). Required for the formation of the autophagosome-like double-membrane structure that surrounds the Salmonella-containing vacuole (SCV) during S.typhimurium infection and subsequent xenophagy (By similarity). Involved in repair of DNA damage caused by ionizing radiation, which subsequently improves cell survival by decreasing apoptosis (By similarity). Inhibits PTK2/FAK1 and PTK2B/PYK2 kinase activity, affecting their downstream signaling pathways (PubMed:10769033, PubMed:12221124). Plays a role as a modulator of TGF-beta-signaling by restricting substrate specificity of RNF111 (By similarity). Functions as a DNA-binding transcription factor (PubMed:12095676). Is a potent regulator of the RB1 pathway through induction of RB1 expression (PubMed:14533007). Plays a crucial role in muscular differentiation (PubMed:12163359). Plays an indispensable role in fetal hematopoiesis and in the regulation of neuronal homeostasis (By similarity).

关联

100 项与 RB1CC1 相关的临床结果

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100 项与 RB1CC1 相关的转化医学

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0 项与 RB1CC1 相关的专利（医药）

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项与 RB1CC1 相关的文献（医药）

2024-03-04·The Journal of cell biology

The V-ATPase-ATG16L1 axis recruits LRRK2 to facilitate the lysosomal stress response.

Article

作者: Tomoya Eguchi ; Maria Sakurai ; Yingxue Wang ; Chieko Saito ; Gen Yoshii ; Thomas Wileman ; Noboru Mizushima ; Tomoki Kuwahara ; Takeshi Iwatsubo

Leucine-rich repeat kinase 2 (LRRK2), a Rab kinase associated with Parkinson's disease and several inflammatory diseases, has been shown to localize to stressed lysosomes and get activated to regulate lysosomal homeostasis. However, the mechanisms of LRRK2 recruitment and activation have not been well understood. Here, we found that the ATG8 conjugation system regulates the recruitment of LRRK2 as well as LC3 onto single membranes of stressed lysosomes/phagosomes. This recruitment did not require FIP200-containing autophagy initiation complex, nor did it occur on double-membrane autophagosomes, suggesting independence from canonical autophagy. Consistently, LRRK2 recruitment was regulated by the V-ATPase-ATG16L1 axis, which requires the WD40 domain of ATG16L1 and specifically mediates ATG8 lipidation on single membranes. This mechanism was also responsible for the lysosomal stress-induced activation of LRRK2 and the resultant regulation of lysosomal secretion and enlargement. These results indicate that the V-ATPase-ATG16L1 axis serves a novel non-autophagic role in the maintenance of lysosomal homeostasis by recruiting LRRK2.

2024-02-21·European journal of clinical investigation

Loss of CEACAM1 in hepatocytes causes hepatic fibrosis.

Article

作者: Sobia Zaidi ; Suman Asalla ; Harrison T Muturi ; Lucia Russo ; Raziyeh Abdolahipour ; Getachew Debas Belew ; Maria Benitez Iglesias ; Mary Feraudo ; Lensay Leon ; Enoch Kuo ; Xiuli Liu ; Sivarajan Kumarasamy ; Hilda E Ghadieh ; Cara Gatto-Weis ; Ali Zarrinpar ; Sergio Duarte ; Sonia M Najjar

BACKGROUND:

The role of insulin resistance in hepatic fibrosis in Metabolic dysfunction-Associated SteatoHepatitis (MASH) remains unclear. Carcinoembryonic Antigen-related Cell Adhesion Molecule1 protein (CEACAM1) promotes insulin clearance to maintain insulin sensitivity and repress de novo lipogenesis, as bolstered by the development of insulin resistance and steatohepatitis in AlbuminCre + Cc1^fl/fl mice with liver-specific mouse gene encoding CEACAM1 protein (Ceacam1) deletion. We herein investigated whether these mice also developed hepatic fibrosis and whether hepatic CEACAM1 is reduced in patients with MASH at different fibrosis stages.

METHODS:

AlbuminCre + Cc1^fl/fl mice were fed a regular or a high-fat diet before their insulin metabolism and action were assessed during IPGTT, and their livers excised for histochemical, immunohistochemical and Western blot analysis. Sirius red staining was used to assess fibrosis, and media transfer was employed to examine whether mutant hepatocytes activated hepatic stellate cells (HSCs). Hepatic CEACAM1 protein levels in patients with varying disease stages were assessed by ELISA.

RESULTS:

Hepatocytic deletion of Ceacam1 caused hyperinsulinemia-driven insulin resistance emanating from reduced hepatic insulin clearance. AlbuminCre + Cc1^fl/fl livers showed inflammation, fibrosis and hepatic injury, with more advanced bridging and chicken-wire hepatic fibrosis under high-fat conditions. Media transferred from hepatocytes isolated from mutant mice activated control HSCs, likely owing to their elevated endothelin1 content. Interestingly, hepatic CEACAM1 levels were lower in the livers of patients with MASH and declined gradually with advanced fibrosis stage.

CONCLUSIONS:

Hepatic CEACAM1 levels declined with progression of MASH in humans. The phenotype of AlbuminCre + Cc1^fl/fl mice assigned a key role to CEACAM1 loss from hepatocytes in hepatic fibrosis independently of other liver cells.

2024-02-17·Nature communications

ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.

Article

作者: Taeko Sasaki ; Yasuharu Kushida ; Takuya Norizuki ; Hidetaka Kosako ; Ken Sato ; Miyuki Sato

Allophagy is responsible for the selective removal of paternally inherited organelles, including mitochondria, in Caenorhabditis elegans embryos, thereby facilitating the maternal inheritance of mitochondrial DNA. We previously identified two key factors in allophagy: an autophagy adaptor allophagy-1 (ALLO-1) and TBK1/IKKε family kinase IKKE-1. However, the precise mechanisms by which ALLO-1 and IKKE-1 regulate local autophagosome formation remain unclear. In this study, we identify two ALLO-1 isoforms with different substrate preferences during allophagy. Live imaging reveals a stepwise mechanism of ALLO-1 localization with rapid cargo recognition, followed by ALLO-1 accumulation around the cargo. In the ikke-1 mutant, the accumulation of ALLO-1, and not the recognition of cargo, is impaired, resulting in the failure of isolation membrane formation. Our results also suggest a feedback mechanism for ALLO-1 accumulation via EPG-7/ATG-11, a worm homolog of FIP200, which is a candidate for IKKE-1-dependent phosphorylation. This feedback mechanism may underlie the ALLO-1-dependent initiation and progression of autophagosome formation around paternal organelles.

项与 RB1CC1 相关的新闻（医药）

2023-12-20

·今日头条

再取进展！复旦大学发现肝内胆管癌靶向治疗新策略

本文为转化医学网原创，转载请注明出处作者：Jerry 导读： CD133在多种肿瘤中被广泛用作分离肿瘤起始细胞的标志物。然而，CD133 n -糖基化与干细胞特性之间的关系尚不清楚。近日，复旦大学研究团队在期刊《Cell Reports》上发表了题为“Loss of α-1,2-mannosidase MAN1C1 promotes tumorigenesis of intrahepatic cholangiocarcinoma through enhancing CD133-FIP200 interaction”的研究论文，本研究中，研究人员发现肝内胆管癌(ICCA)组织中α 1,2-甘露糖基化CD133的水平与干性基因的水平相关。α 1,2-甘露糖修饰的CD133+细胞具有肿瘤起始细胞的特征。α 1,2-甘露糖基化的CD133是ICCA起始细胞的功能标志物。 https://www-cell-com.libproxy1.nus.edu.sg/cell-reports/fulltext/S2211-1247(23)01600-5#%20 研究背景 01 肿瘤起始细胞(TICs)与肿瘤的发生、复发和转移密切相关。因此，TICs被认为是最有希望的肿瘤治疗靶点。迄今为止，TICs的鉴定主要基于表面标记。CD133是一种五跨膜糖蛋白，已被广泛用作分离TICs的标志物，包括肝癌、胶质瘤和结肠癌。而CD133在干细胞和分化细胞上均有表达。越来越多的证据表明，CD133表面n -糖链结构与干细胞特性相关。在肿瘤干细胞分化过程中，CD133表面n -糖链结构发生变化。缺氧可增强胶质瘤干细胞中CD133的糖基化。此外，改变CD133的糖基化会影响其稳定性或功能。n -糖基化复合物通过增强CD133与TSG101的相互作用促进CD133的分泌。缺氧诱导糖基转移酶8结构域1 (GLT8D1)通过抑制CD133降解促进胶质瘤干细胞维持。然而，CD133的n -糖链结构与干细胞特性之间的关系尚不清楚。肝内胆管癌(ICCA)是第二常见的肝癌。ICCA的5年生存率为9%。由于复发率高，ICCA仍然是一种棘手的疾病。ICCA与超重/肥胖和慢性肝病(包括肝硬化和/或病毒性肝炎)有关。必须探索ICCA的分子机制，以开发新的治疗策略。鉴定ICCA起始细胞的标记物可能有助于ICCA靶向治疗的发展。虽然CD133的表达与ICCA的转移和低存活率有关，但CD133在鉴别ICCA启动细胞中的作用尚不清楚。研究进展 02 研究人员评估了MAN1C1在ICCA中的表达特征。免疫组化分析显示，MAN1C1在各种正常组织中均有表达。在TCGA数据集中，MAN1C1的表达在包括胆管癌在内的肿瘤样本子集中显著降低。MAN1C1的低表达与各种癌症的不良预后相关。因此，低MAN1C1表达与癌症进展有关。接下来，研究人员评估α-1,2- MAN是否有助于ICCA启动细胞的特性。肿瘤干细胞(Cancer stem cells, CSCs)主要存在于低糖或营养储存的微环境中。在1-2代低糖条件下，异位表达FLAG标记的MAN1C1显著减少α-1,2- man +CD133+细胞的球形成。极限稀释分析被广泛应用于干细胞频率的测定。通过体外有限稀释实验，研究人员发现MAN1C1过表达抑制了CD133+α-1,2- man +细胞的干细胞活性。MAN1C1的异位表达抑制了CD133+α-1,2- man +细胞的肿瘤启动能力，提高了肿瘤小鼠的存活率。总之，通过MAN1C1过表达抑制α-1,2- man修饰抑制了ICCA启动细胞的自我更新和肿瘤发生。通过MAN1C1过表达抑制α-1,2- man可抑制ICCA启动细胞的肿瘤发生 FIP200是哺乳动物细胞自噬体形成所必需的。在营养剥夺或缺氧的情况下，自噬维持tic的自我更新。α-1,2-MAN对ICCA启动细胞自噬的作用。LC3-I向LC3-II的转化被用作自噬激活的指标。MAN1C1过表达显著降低CD133+α-1,2- man +细胞中LC3-II与LC3-I的比值。当自噬被激活时，绿色荧光蛋白连接LC3 (GFP-LC3)集中在自噬液泡中形成点状绿色荧光。MAN1C1的异位表达减少了GFP-LC3小点的形成。总的来说，MAN1C1减少了ICCA启动细胞的自噬。 α-1,2- MAN通过上调自噬基因FIP200增强ICCA启动细胞的自我更新和肿瘤发生能力接下来，研究人员评估了FIP200在man1c1降低的自噬中的作用。FIP200的异位表达阻断了MAN1C1对CD133+α-1,2- man +细胞自噬的负性作用，MAN1C1过表达对CD133+α-1,2- man +细胞自我更新的抑制作用被FIP200过表达部分挽救。过表达FIP200可逆转MAN1C1对CD133+α 1,2- man +细胞的抑制作用。综上所述，α 1,2- man通过上调FIP200的表达来增强肝内胆管癌起始细胞的自我更新和成瘤能力。研究结论 03 综上所述，CD133 α-1,2-甘糖基化是ICCA启动细胞的功能标志物，为TIC提供了更特异性的标志物。本发现提供了CD133的n -聚糖结构与干细胞特性之间的关系，并提供了消除ICCA启动细胞的新策略。参考资料： https://www-cell-com.libproxy1.nus.edu.sg/cell-reports/fulltext/S2211-1247(23)01600-5#%20 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布）点击对应文字查看详情

临床研究

2023-01-26

·佰傲谷BioValley

CD8+ T细胞通过炎症驱动大脑衰老

大脑中枢神经系统(CNS)衰老的表现之一是功能退化，即神经退行性变化。虽然神经退行性衰老的过程受到许多因素的影响，不过其表现通常包括白质体积和功能下降。CD8+ T细胞与神经退行性变化的关系在MCI和AD中，CD8+ T++EMRA细胞与认知存在负相关，与其中Tcm和Tem的占比正相关。Nature 577, 399–404 (2020). 轴突-髓鞘单位和突触末端是最容易受到衰老相关恶化影响的神经结构。通常先天免疫细胞浸润较多。在周围神经系统的衰老过程中，巨噬细胞是髓鞘纤维和运动终板结构和功能下降的主要驱动因素。在中枢神经系统的衰老过程中，小胶质细胞促进髓鞘轴突和突触的损伤，发展处更具炎症性的表型。表现为：大脑内促炎细胞因子增加，小胶质细胞上炎症受体的表达增加。同时还能够翻译和传播在外周启动的炎症信号。白质中的CD8 + T细胞主要包括：CD62L+ CX3CR1-中央记忆型T细胞(Tcm)：高表达IL7R，大部分低表达PD-1。CD62L-CX3CR1+ T细胞(Teff)；剩余的CD62L- CX3CR1-细胞：大多数是IL7R+CD103-细胞，部分为IL7R-CD103-和IL7R+CD103+。其中的组织驻留记忆T细胞：均表达CD69。40%的CD8+ T细胞表达PD-1，32%的CD8+ T细胞表达LAG-3。在衰老过程中，CD8 + CNS相关T细胞上的PD-1表达增加。细胞毒性CD8+ Teff是疾病的触发因素之一。在空间上，其与并列结节，前瞻性损伤部位相关；与M1极化小胶质细胞相互作用。M1极化小胶质细胞不仅产生促炎剂，而且通过骨髓细胞识别分子和促炎激活标志物Sn抑制CD8+ CD122+ Treg细胞。诱导少突胶质细胞的反应性和损失。少突胶质细胞(oligodendrocyte)作为髓鞘的主要组成部分，其丢失会导致神经元功能障碍，引起MS等疾病，在大脑缓慢衰老或者自身免疫攻击的过程中，少突胶质细胞会被消除。靶向老年人CD8+ CNST细胞可能会减轻与衰老相关的大脑结构和功能下降。其具体表现包括：CD8+ T细胞以TCR和颗粒酶B依赖的方式驱动轴突变性。小鼠模型显示全身炎症可以促进衰老中枢神经系统中CD8+ T细胞驱动的轴索变性。老年大脑中CD3+ T细胞几乎只存在于白质中，富集在侧脑室附近的区域。白质富含髓鞘与神经元轴突，对神经元连接至关重要。Glia. 2017 Sep;65(9):1407-1422.CD8+ T细胞引发的炎症连锁反应是这些神经退行性变化的主要驱动因素。在衰老大脑中，T细胞和DC通过上调反应性星形胶质细胞和小胶质细胞来促进一般的炎症表现。B细胞和肥大细胞则不会导致这种炎症反应。目前认为，CD8+ T细胞通过IFN-γ诱导IFN反应性小胶质细胞来引发神经退行，在脑室下区神经源性小生境内驱动IFN信号传导。衰老白质中，IFN反应性少突胶质细胞(STAT1+ CC1+)更明显地定位在CD8+ T附近，反之亦然。与Serpin3n+CC1+少突胶质细胞形成对比。Nat Neurosci. 2022 Nov;25(11):1446-1457.衰老大脑中，CD8+ 细胞毒性T细胞是IFN-γ的主要来源。IFN-γ对少突胶质细胞、小胶质细胞和神经元干细胞有直接作用。因此，CD8+ T细胞可能参与杀死少突胶质细胞并靶向轴突连接。IFN-γ介导极化的小胶质细胞促进对少突胶质细胞的杀伤。由活化小胶质细胞和活性星形胶质细胞启动的其他机制将产生其他促炎细胞因子(例如，TNF，IL-1β， IL-6, IL-12和IL-23)。不过其导致神经退行性变的具体机制尚不明确。不过目前尚不能排除其他IFN是否也有类似贡献。同时浸润的CD8+ T细胞同时也分泌TNF和MCP-1/CCL2等。Nat Immunol 24, 12–13 (2023).因此可以认为，IFN反应性少突胶质细胞在衰老白质中积极招募促炎小胶质细胞作为效应细胞。CD8 T细胞数量与小胶质细胞促炎功能降低之间存在正相关。衰老小胶质细胞促炎反过来重编程促进浸润：通过对TCRvβ库使用情况的分析表明，外周CD8+ T细胞进入中枢神经系统的过程很可能是随机的。目前认为衰老的小胶质细胞能够改变其表型以促进浸润。小鼠模型中：老年小胶质细胞释放趋化因子CCL3以募集外周CD8+ 记忆T细胞。此外，老年小胶质细胞向促炎状态转变，释放TNF-α上调VCAM1和ICAM1在脑静脉内皮细胞中的表达，从而促进外周T细胞经内皮迁移。体外显示，消耗小胶质细胞或阻断CCL3可以部分减少老年脑切片招募的CD8 T细胞的数量。人体中：体外实验表明，当用老年人的脑脊液治疗时，人小胶质细胞也会转变为趋化表型。Immun Ageing 19, 34 (2022).小结谈到大脑衰老和神经退行性变化，近年来最受关注的尤属阿尔茨海默症。FDA通过两款受到争议的抗体疗法，或许也说明还是具有紧迫的未满足临床需求和一定的商业化价值。CTL和慢性炎症在很多疾病中均有出现，不知道是否能够提供一种更普适的思路，甚至通过善用“旧药”等以达到改善目的。参考文献：1.Liston, A., Yshii, L. T cells drive aging of the brain. Nat Immunol 24, 12–13 (2023). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41590-022-01390-02.Kaya T, et al. CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging. Nat Neurosci. 2022 Nov;25(11):1446-1457. doi: 10.1038/s41593-022-01183-6. Epub 2022 Oct 24. PMID: 36280798; PMCID: PMC9630119.3.Zhang, X., Wang, R., Chen, H. et al. Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches. Immun Ageing 19, 34 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1186/s12979-022-00289-64.Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol. 2013 Feb;39(1):19-34. doi: 10.1111/j.1365-2990.2012.01306.x. PMID: 23039106; PMCID: PMC3553257.5.Groh J, Martini R. Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment. Glia. 2017 Sep;65(9):1407-1422. doi: 10.1002/glia.23162. Epub 2017 Jun 1. PMID: 28568966.6.Stichel CC, Luebbert H. Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol Aging. 2007 Oct;28(10):1507-21. doi: 10.1016/j.neurobiolaging.2006.07.022. Epub 2006 Sep 7. PMID: 16959379.7.Ritzel RM, Crapser J. Age-Associated Resident Memory CD8 T Cells in the Central Nervous System Are Primed To Potentiate Inflammation after Ischemic Brain Injury. J Immunol. 2016 Apr 15;196(8):3318-30. doi: 10.4049/jimmunol.1502021. Epub 2016 Mar 9. PMID: 26962232; PMCID: PMC4868658.8.Groh, J., Knöpper, K., Arampatzi, P. et al. Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nat Aging 1, 357–367 (2021). https://doi-org.libproxy1.nus.edu.sg/10.1038/s43587-021-00049-z9.Gate, D., Saligrama, N., Leventhal, O. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-019-1895-7近期热门视频更多精彩视频，尽在佰傲谷视频号，欢迎关注~本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀‍ 点亮在看，传递信息♥

临床1期