TRIM26

更新于：2025-05-07

基本信息

别名

Acid finger protein、AFP、RING finger protein 95

+ [6]

简介

E3 ubiquitin-protein ligase which regulates the IFN-beta production and antiviral response downstream of various DNA-encoded pattern-recognition receptors (PRRs). Plays also a central role in determining the response to different forms of oxidative stress by controlling levels of DNA glycosylases NEIL1, NEIL3 and NTH1 that are involved in repair of damaged DNA (PubMed:29610152, PubMed:36232914). Promotes nuclear IRF3 ubiquitination and proteasomal degradation (PubMed:25763818). Bridges together TBK1 and NEMO during the innate response to viral infection leading to the activation of TBK1. Positively regulates LPS-mediated inflammatory innate immune response by catalyzing the 'Lys-11'-linked polyubiquitination of TAB1 to enhance its activation and subsequent NF-kappa-B and MAPK signaling (PubMed:34017102). In a manner independent of its catalytic activity, inhibits WWP2, a SOX2-directed E3 ubiquitin ligase, and thus protects SOX2 from polyubiquitination and proteasomal degradation (PubMed:34732716). Ubiquitinates the histone acetyltransferase protein complex component PHF20 and thereby triggers its degradation in the nucleus after its recruitment by the histone demethylase KDM6B, serving as a scaffold protein (PubMed:23452852). Upon induction by TGF-beta, ubiquitinates the TFIID component TAF7 for proteasomal degradation (PubMed:29203640). Induces ferroptosis by ubiquitinating SLC7A11, a critical protein for lipid reactive oxygen species (ROS) scavenging (By similarity). Inhibits directly hepatitis B virus replication by mediating HBX ubiquitination and subsequent degradation (PubMed:35872575). (Microbial infection) Promotes herpes simplex virus type 2/HHV-2 infection in vaginal epithelial cells by decreasing the nuclear localization of IRF3, the primary mediator of type I interferon activation.

关联

100 项与 TRIM26 相关的临床结果

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100 项与 TRIM26 相关的转化医学

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0 项与 TRIM26 相关的专利（医药）

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项与 TRIM26 相关的文献（医药）

2025-03-01·Journal of Biological Chemistry

Melatonin-mediated cGAS-STING signal in senescent macrophages promote TNBC chemotherapy resistance and drive the SASP

Article

作者: Zhuang, Minyu ; Liu, Xiaoan ; Yu, Xiafei ; Zhang, Xiaoqiang ; Tao, Jing ; Yang, Junzhe ; Wu, Xian ; Zhu, Yanhui ; Zhang, Hongfei

The build-up of senescent cells in tissues is a key indicator of aging, associated with negative prognosis and therapy resistance. Despite immune dysfunction related to aging, also known as immunosenescence, is recognized as a factor in this process, the exact mechanisms are still unclear. In this study, we reported that melatonin deficiency accelerated macrophage senescence in triple-negative breast cancer (TNBC), whereas, melatonin could defend macrophages against senescence through the Nfatc1-Trim26-cgas-Sting pathway. Mechanistically, melatonin enhanced the nuclear translocation of Nfatc1 and elevated Trim26 transcription levels. Trim26, functioning as an E3 ligase, ubiquitinates cgas, thereby inhibiting the activation of the cgas-Sing pathway and consequently preventing cell senescence. Conversely, melatonin deficiency induced cgas-Sting pathway activation to promote macrophage aging. Our results show that melatonin inhibited macrophage senescence and improved chemotherapy responsiveness, with further enhancement when combined with the cgas inhibitor (G150). Overall, our findings indicated that melatonin protects macrophages from immunosenescence, suggesting its therapeutic potential for enhancing chemotherapy response.

2025-01-01·Heliyon

TRIM26 exacerbates pathological cardiac hypertrophy by activating TAK1

Article

作者: Shan, Huajing ; Tian, Han ; Chen, Shaoze ; Zhang, Jianqing ; Jin, Zhaoxia ; Dong, Bizhen ; Xia, Xiaochuang ; Xu, Chengsheng ; Liu, Yemao ; Ma, Tengfei

Pathological myocardial hypertrophy can induce heart failure with high mortality, it is necessary to explore its pathogenesis. Tripartite motif-containing 26 (TRIM26) belongs to the multidomain E3 ubiquitin ligase family. We observed increased expression of TRIM26 in the myocardium of C57BL/6 mice subjected to transverse aortic constriction (TAC) surgery and neonatal rat cardiomyocytes (NRCMs) treated with phenylephrine (PE). To evaluate the role of TRIM26 in pathological cardiac hypertrophy, we generated Trim26 global knockout mice and Trim26 overexpression adenoviruses. Mice with Trim26 deletion showed alleviated cardiomyocyte enlargement, inflammation, fibrosis, and cardiac dysfunction after TAC surgery. In PE-treated NRCMs, Trim26 overexpression promoted cardiomyocyte enlargement and inflammation, while Trim26 knockdown had the opposite effects. RNA sequencing and molecular biology methodologies were performed to identify targets conducive to TRIM26 function. The results showed that TRIM26 activated the transforming growth factor-beta activated kinase 1 (TAK1)-c-Jun N-terminal kinase/p38 signaling pathway in response to hypertrophic stress. Moreover, inhibition of TAK1 activation can reverse the promotion effect of TRIM26 overexpression on cardiomyocyte hypertrophy induced by PE stimulation in vitro. Our study demonstrated that TRIM26 plays an active role in pathological cardiac hypertrophy, and the TRIM26-TAK1 pathway may represent a therapeutic target for treating pathological cardiac hypertrophy and heart failure.

2024-12-10·Analytical Chemistry

TAggiXL: A Fluorescence-Traceable Cross-Linking Strategy for Unbiased Profiling of Protein Aggregation and Interactome Dynamics

Article

作者: Zhang, Lihua ; Liu, Yu ; Gong, Zhou ; Chen, Yuwen ; Zhang, Yukui ; Li, Zhiying ; Chen, Jing ; Pan, Hui ; Liang, Zhen ; Zhao, Qun ; An, Yuxin

Protein aggregation is a hallmark of numerous degenerative diseases, yet its underlying mechanisms remain poorly understood due to the challenges in identifying the composition and interaction networks of these aggregates. To address this issue, we developed TAggiXL, a novel method that combines fluorescence-traceable aggregate isolation with cross-linking proteomics, significantly enhancing the efficiency and precision of isolating protein aggregates. This method facilitates unbiased profiling of aggregated proteomes and their interactomes in live cells. The TAggiXL approach leverages advanced cross-linking proteomics, density gradient centrifugation, and fluorescence tracking to provide detailed characterization of protein aggregation under various stress conditions including HSP90 and proteasome inhibition. Using TAggiXL, we identified key components and interactions within the aggregates, particularly highlighting E3 ubiquitin ligase TRIM26, which plays a crucial role in aggregate formation and autophagic clearance under stress and pathogenic conditions. Moreover, TAggiXL revealed that HSPA1B functions as a central interaction hub within the aggregated proteome. It preferentially interacts with intrinsically disordered regions (IDRs) of aggregate components and demonstrates dynamic behavior within the aggregate. In summary, TAggiXL offers a powerful tool for dissecting the complex composition and interaction networks of protein aggregates, with a significant potential to advance our understanding of protein aggregation in degenerative diseases. It also holds promise for the development of future therapeutic interventions.

项与 TRIM26 相关的新闻（医药）

2024-08-12

·今日头条

曹雪涛团队再取突破：干预癌症和病毒感染的潜在靶点

【导读】 IRF3是介导抗病毒先天免疫反应的核心因子，泛素化对IRF3的蛋白酶体周转至关重要。然而，IRF3泛素化对先天免疫的精确激活和及时解决的时空调控尚不清楚。 2024年8月8日，海军军医大学/中国医学科学院/北京协和医学院/南开大学曹雪涛团队合作在期刊《Cell Reports 》上发表了题为”The deubiquitinase BAP1 and E3 ligase UBE3C sequentially target IRF3 to activate and resolve the antiviral innate immune response“的研究论文，该研究发现BRCA1相关蛋白-1 (BAP1)和泛素蛋白连接酶E3C (UBE3C)是病毒感染期间控制IRF3稳定性的关键去泛素酶和泛素酶。 https://doi.org/10.1016/j.celrep.2024.114608 背景知识 01 固有信号的有效激活对于宿主对入侵病原体的反应至关重要。干扰素调节因子3 (IRF3)在多种免疫细胞中组成性表达，在抗病毒固有应答中I型干扰素(IFN)的产生中起重要作用。在正常条件下，IRF3以单体形式存在。病毒感染后，IRF3的C端结构域(CTD)被磷酸化，导致其同源二聚化并转位至细胞核，在细胞核内与共激活因子creb结合蛋白CBP/p300形成转录调节复合体，激活I型IFN和IFN刺激基因(ISGs)的转录。IRF3和IFN的充分活化是有效清除入侵病毒所必需的。然而，适当终止IRF3激活和IFN生成对于避免免疫病理(包括ⅰ型干扰素病，如系统性红斑狼疮)也至关重要。因此，IRF3活性的精确时间调控对于有效清除病毒同时避免免疫病理损伤至关重要。许多翻译后修饰被报道可以调节IRF3的激活，包括磷酸化、泛素化、甲基化、乙酰化、类泛素化和ISG化。泛素化显著影响IRF3的稳定性和活性，影响抗病毒免疫。IRF3的K63多泛素化对于IRF3的激活是至关重要的，因为用K63R突变体取代野生型泛素(Ub)会抑制IRF3的激活。据报道，E3连接酶RAUL (UBE3C [ub -蛋白连接酶E3C])、c-Cbl、TRIM26和RACK可介导IRF3的K48泛素化，导致其蛋白酶体降解，并作为"制动器"停止I型IFN的产生。适当阶段的“制动”有助于炎症和组织损伤的缓解，但过早制动I型IFN会损害宿主的抗病毒免疫。然而，这些E3泛素化酶对IRF3的精确时空调控仍不清楚。目前还没有E3连接酶特异性地参与感染和炎症消退的后期阶段。因此，仍然需要深入了解E3连接酶模块对IRF3稳定性的调节作用。 BAP1介导IRF3在Lys77上的去泛素化 02 为了鉴定k48连接的IRF3泛素化关键位点，研究人员构建了位点特异性的赖氨酸到精氨酸的突变体，其中14个潜在的泛素化位点在人和小鼠之间是保守的。K77R和K87R显著恢复了IRF3的降解，表明这些可能是聚泛素化位点。K77/87R双突变体进一步减弱了IRF3的降解。所有突变体均保留了与BAP1的结合能力。此外，这些IRF3突变进一步激活IFN-β转录和IRF3二聚化。由于Lys77和Lys87位于IRF3的功能性NLS中，研究人员通过共聚焦显微镜评估了K-R突变对IRF3易位的潜在影响。IRF3野生型与K-R突变型的核易位无明显差异。然而，K-A突变完全消除了其核易位，可能是由于精氨酸同赖氨酸一样也是碱性氨基酸，K-A突变破坏了氨基酸的电荷。这也与之前报道的KR77/78NG和RK86/87LQ突变不能诱导IRF3核易位一致。因此，所有这些数据表明，K77和K87是IRF3泛素化和降解的关键位点。 BAP1使IRF3在Lys77上去泛素化研究人员进一步探索了BAP1靶向的潜在去泛素化位点。BAP1过表达减弱了除K77R外所有突变体中k48连接的多泛素化，这表明BAP1可能特异性介导了IRF3在Lys77上的去泛素化。此外，BAP1增加了野生型IRF3和K87R诱导的IFN-β转录，但在K77R突变体中未观察到这种差异(K77R和K77/ 87r)，提示K77位点是BAP1作用的关键。因此，BAP1特异性地介导了IRF3在Lys77上的去泛素化。 BAP1和E3连接酶UBE3C依次结合IRF3并在抗病毒反应中调节Lys77泛素化 03 据报道，几种E3连接酶可介导k48连接的IRF3多泛素化，包括TRIM26、RBCK1、UBE3C和c-Cbl。UBE3C促进k48 -连接的多聚泛素化K87R和野生型IRF3，但不促进K77R和K77/87R IRF3。此外，TRIM26促进k48连接的多聚泛素化的K77R和野生型IRF3，但不促进K87R或K77/87R IRF3。这些结果表明，trim26介导的k48连接的IRF3在Lys87和UBE3C上的多聚泛素化对Lys77泛素化具有特异性。RBCK1和c-Cbl对Lys77和Lys87泛素化均有促进作用，但作用程度较低。 UBE3C在细胞质和细胞核中均有表达，病毒感染后UBE3C在细胞核中富集。而UBE3C在细胞核内特异性地促进了k48连接的IRF3多泛素化。为了进一步明确BAP1和UBE3C在调节IRF3的k48连接多泛素化中的关系，研究人员评估了UBE3C和BAP1在病毒感染过程中的表达动力学。与之相反，UBE3C的表达从感染后12 h开始增加，16 h达到峰值;IRF3的磷酸化在感染后4 h达到峰值，IRF3的二聚体化和核转位在感染后8 h达到峰值，两者均与BAP1的表达一致，但先于UBE3C的表达。这些结果表明，BAP1和UBE3C可能序贯调控k48连接的IRF3多泛素化。为了验证这一假设，研究人员评估了病毒感染期间UBE3C-IRF3和BAP1-IRF3相互作用的动力学。数据显示，BAP1-IRF3(4-12小时)和UBE3C-IRF3(12-20小时)的相互作用在病毒感染过程中被顺序调节。为了确定BAP1和UBE3C的上调是否依赖于I型IFN的产生，研究人员将野生型、Irf3缺陷型和ifnar1缺陷型小鼠的原代巨噬细胞感染VSV。病毒感染后，Irf3−/−和Ifnar1−/−巨噬细胞中UBE3C的上调消失，而BAP1的上调未见改变，表明I型IFN信号在感染后上调UBE3C。因此，病毒感染后，BAP1和UBE3C可能序贯调控IRF3活性。感染后早期，BAP1表达上调，促进IRF3去泛素化，从而促进抗病毒固有免疫。但在感染后期，I型IFN可能以反馈方式诱导UBE3C表达，并取代BAP1与IRF3相互作用，从而有助于缓解炎症，避免免疫发病机制。研究结论 04 综上所述，研究人员发现肿瘤抑制基因BAP1可以增强抗病毒固有免疫应答。在机制上，通过去除IRF3 Lys77上的k48连接的多泛素链并防止IRF3被蛋白酶体降解，IRF3信号通路得到加强。本研究结果还揭示了E3泛素连接酶UBE3C和BAP1可以共同调节IRF3的功能。这些发现进一步扩展了研究人员对IRF3表达和功能的调控网络的认识，为肿瘤抑制因子BAP1的生物学功能提供了新的见解，并发现了一个潜在的干预癌症和病毒感染的靶点。【参考资料】 https://doi.org/10.1016/j.celrep.2024.114608 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 线上｜08月15日 19:00-20:30 ▶ “脑类器官前沿：揭秘遗传机制，重塑神经退行性疾病研究未来”线上研讨会欢迎您的参与！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会欢迎您的参与！点击对应文字查看详情

蛋白降解靶向嵌合体

2023-12-20

·生物谷

南京医科大学研究者们提出了一种治疗胶质瘤的潜在策略

铁死亡是一种由细胞膜上脂质过氧化物的毒性积累引起的非凋亡性细胞死亡形式，广泛参与包括癌症在内的许多疾病的病理生理过程。铁死亡是一种由细胞膜上脂质过氧化物的毒性积累引起的非凋亡性细胞死亡形式，广泛参与包括癌症在内的许多疾病的病理生理过程。GPX4是八种谷胱甘肽过氧化物酶(谷胱甘肽过氧化物酶)之一，通过解毒细胞脂质过氧化而成为铁死亡的核心调节因子。越来越多的证据表明，抑制gpx4介导的铁死亡是一种很有前景的癌症治疗策略。虽然GPX4在铁死亡中的重要作用已经得到了很好的证实，但其转录后修饰(PTMs)的机制仍然知之甚少。图片来源： https://pubmed.ncbi.nlm.nih.gov/37872147/ 近日，来自南京医科大学的研究者们在Cell Death Dis.杂志上发表了题为“The E3 ligase TRIM26 suppresses ferroptosis through catalyzing K63-linked ubiquitination of GPX4 in glioma”的文章，该研究确定了GPX4 k63相关的多泛素化在铁死亡中的作用，并提出了一种治疗胶质瘤的潜在策略。含硒酶GPX4作为铁死亡的中心调节剂，铁死亡是一种由脂质过氧化引起的铁依赖性非凋亡形式的细胞死亡。然而，对其转录后修饰的调控机制知之甚少。在这里，研究者鉴定了含有三方基序的蛋白TRIM26是GPX4的E3泛素连接酶。 TRIM26通过其环结构域直接与GPX4相互作用，催化GPX4在K107和K117位点的泛素化，促进GPX4从K48到K63的泛素化转换，从而增强GPX4蛋白的稳定性。此外，plk1介导的TRIM26的S127磷酸化增强了TRIM26与GPX4之间的相互作用。抑制TRIM26磷酸化导致GPX4 k63相关的多泛素化减少，并降低肿瘤细胞中GPX4蛋白水平。进一步研究发现TRIM26在胶质瘤细胞中过表达。在体内和体外实验中，TRIM26的沉默显著地阻碍胶质瘤对铁的抵抗和肿瘤的发生。临床上，在胶质瘤样本中，TRIM26的表达与GPX4和PLK1水平直接相关，并与胶质瘤患者预后不良相关。 TRIM26、GPX4与PLK1的临床相关性图片来源：https://pubmed.ncbi.nlm.nih.gov/37872147/ 综上所述，GPX4经历了trim26介导的K63-linked多泛素化，其拮抗GPX4 K48-linked多泛素化和降解。此外，plk1依赖的TRIM26的S127磷酸化对于TRIM26和GPX4之间的相互作用至关重要。破坏PLK1-TRIM26-GPX4轴通过促进铁死亡抑制胶质瘤的发生，提示一种潜在的治疗胶质瘤的策略。(生物谷 Bioon.com）参考文献 Zhangjie Wang et al. Cell Death Dis. The E3 ligase TRIM26 suppresses ferroptosis through catalyzing K63-linked ubiquitination of GPX4 in glioma. 2023 Oct 23;14(10):695. doi: 10.1038/s41419-023-06222-z.