UFD1

更新于：2025-01-23

基本信息

别名

UB fusion protein 1、Ubiquitin fusion degradation protein 1、ubiquitin recognition factor in ER associated degradation 1

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简介

Essential component of the ubiquitin-dependent proteolytic pathway which degrades ubiquitin fusion proteins. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. It may be involved in the development of some ectoderm-derived structures (By similarity). Acts as a negative regulator of type I interferon production via the complex formed with VCP and NPLOC4, which binds to RIGI and recruits RNF125 to promote ubiquitination and degradation of RIGI (PubMed:26471729).

关联

100 项与 UFD1 相关的临床结果

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100 项与 UFD1 相关的转化医学

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0 项与 UFD1 相关的专利（医药）

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265

项与 UFD1 相关的文献（医药）

2025-01-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Trim21 modulates endoplasmic reticulum-associated degradation and sensitizes cancer cells to ER stress-induced apoptosis by inhibiting VCP/Npl4/UFD1 assembly

Article

作者: Quan, Yi ; Wang, Fuqing ; Liao, Yanli ; Yu, Xin ; Li, Duanzhuo ; Si, WenXia ; Liao, Shengjie ; Huang, Mi ; Yuan, Chao

Endoplasmic reticulum-associated degradation (ERAD) serves as a crucial quality and quantity control system that removes misfolded or unassembled proteins from the Endoplasmic Reticulum (ER) through the cytoplasmic ubiquitin-proteasome system (UPS), which is critical for cell fate decision. ER stress arises when misfolded proteins accumulated within the ER lumen, potentially leading to cell death via proapoptotic unfolded protein response (UPR). UFD1 in associated with VCP-Npl4, is recognized as a key regulator of protein homeostasis in ERAD. However, the factors that control VCP complex assembly remain unclear. The study elucidates the function of Trim21, an E3 ubiquitin ligase, through its interaction with UFD1, facilitating K27-linkage ubiquitination of UFD1 and inhibiting its incorporation into the VCP complex. This results in the suppression of ERAD substrates degradation and the activation of a proapoptotic unfolded protein response in cancer cells. Additionally, Trim21 over-expression enhances ER stress response and promotes apoptosis upon expose to the ER inducer Tunicamycin. Notably, elevated Trim21 expression correlates with improved overall survival in various tumor types. Overall, the findings highlight the critical role of Trim21 in regulating ERAD progression and cell fate determination in cancer cells through modulation of VCP/Npl4/UFD1 complex assembly.

2024-12-17·Proceedings of the National Academy of Sciences

Targeting DTX2/UFD1-mediated FTO degradation to regulate antitumor immunity

Article

作者: Yang, Seungwon ; Kline, Justin ; Wilkinson, Emma ; Zhao, Lijie ; Chen, Jing ; Fan, Hao ; Cui, Yan-Hong ; Applebaum, Mark A. ; Peterson, Jack ; Zou, Zhongyu ; He, Chuan ; Xie, Lishi ; Wei, Jiangbo ; Li, Wenlong ; He, Yu-Ying

Here, we show that vitamin E succinate (VES) acts as a degrader for the m 6 A RNA demethylase fat mass and obesity-associated protein (FTO), thus suppressing tumor growth and resistance to immunotherapy. FTO is ubiquitinated by its E3 ligase DTX2, followed by UFD1 recruitment and subsequent degradation in the proteasome. VES binds to FTO and DTX2, leading to enhanced FTO–DTX2 interaction, FTO ubiquitination, and degradation in FTO-dependent tumor cells. VES suppressed tumor growth and enhanced antitumor immunity and response to immunotherapy in vivo in mouse models. Genetic FTO knockdown or VES treatment increased m 6 A methylation in the LIF (Leukemia Inhibitory Factor) gene and decreased LIF mRNA decay, and thus sensitized melanoma cells to T cell–mediated cytotoxicity. Taken together, our findings reveal the underlying molecular mechanism for FTO protein degradation and identify a dietary degrader for FTO that inhibits tumor growth and overcomes immunotherapy resistance.

2024-10-18·Microbial cell factories

The signal peptide of BmNPV GP64 activates the ERAD pathway to regulate heterogeneous secretory protein expression.

Article

作者: Hao, Bifang ; Li, Mengmeng ; Sun, Luping ; Liu, Na ; Huang, Jinshan ; Xu, Ying

As a powerful eukaryotic expression vector, the baculovirus expression vector system (BEVS) is widely applied to the production of heterogeneous proteins for research and pharmaceutical purposes, while optimization of BEVS remains a work in progress for membrane or secreted protein expression. In this study, the impact of the signal peptide (SP) derived from Bombyx mori nucleopolyhedrovirus (BmNPV) GP64 protein on protein expression, secretion, and the endoplasmic reticulum-associated degradation (ERAD) pathway were investigated in BmN cells and BEVS. Transient expression studies in BmN cells revealed that SP alters the localization and expression levels of recombinant proteins, reducing intracellular accumulation while enhancing secretion efficiency. Quantitative analysis demonstrated that SP-mediated secretion was markedly higher compared to controls, albeit with lower total expression levels. Further exploration into SP-mediated ERAD pathway activation showed increased expression of BiP and other ERAD-associated genes (PDI, UFD1, S1P, and ASK1), correlating with higher SP-driven protein expression levels. RNA interference (RNAi) experiments elucidated that knockdown of ERAD-associated genes enhances both the secretion efficiency of SP-guided proteins and the infectivity of BmNPV. Particularly, interference with BiP demonstrated the most pronounced effect on protein secretion enhancement. Viral infection experiments further supported these findings, showing upregulated ERAD-associated genes during BmNPV infection, indicating their role in viral protein processing and infectivity. In conclusion, this study elucidates the complex interplay between SP-mediated protein secretion, ERAD pathway activation, and viral infectivity in BmNPV-infected cells. These insights suggest strategies for optimizing recombinant protein production and viral protein processing in baculovirus expression systems, with potential implications for biotechnological and biomedical applications. Further research could refine our understanding and manipulation of protein secretion pathways in insect cell-based expression systems.

项与 UFD1 相关的新闻（医药）

2024-12-24

·生物谷

Plos Pathogens | 中国科学院上海免疫与感染研究所肖晖研究组揭示真菌感染的克星！

近日，中国科学院上海免疫与感染研究所肖晖研究组与山东大学基础医学院高成江团队合作在Plos Pathogens杂志上发表了题为" The protein segregase VCP/p97 promotes host antifungal defense via regulation of SYK activation" 的研究论文，揭示了VCP参与抗真菌信号通路Dectin-1调控的新功能和新机制。真菌感染已造成重大公共健康威胁，尤其是艾滋病患者、骨髓移植患者、化疗病人和先天免疫缺陷患者等免疫功能低下者易患真菌感染。尽管已有抗真菌药物, 但是大部分真菌均能产生耐药性，使得真菌血症的致死率超过40%。因此，更好地了解宿主免疫系统尤其是固有免疫系统如何对抗真菌感染对于开发新型的抗真菌感染药物至关重要。尽管以往的研究对Dectin-1信号转导通路进行了初步探讨，但其具体分子机制尚未充分揭示，尤其是在该通路中与酪氨酸磷酸化相关的关键分子的调控机制，尚未被全面识别与解析。本研究采用系统的实验方法，鉴定并验证了应激反应蛋白VCP/p97在Dectin-1信号通路中的关键作用。首先利用ZymD刺激树突状细胞，在不同时间点取样后质谱分析酪氨酸磷酸化的蛋白，筛选出VCP这一新的磷酸化蛋白。进一步研究表明，激活Dectin-1通路能诱导VCP发生酪氨酸磷酸化修饰，且这一磷酸化过程可被酪氨酸激酶抑制剂PP2有效抑制。通过敲低VCP表达或抑制其解聚酶活性，均导致Dectin-1不能有效诱导SYK的磷酸化，并显著降低骨髓来源的巨噬细胞（BMDMs）及树突状细胞（BMDCs）中促炎细胞因子TNF-、IL-6及趋化因子CXCL1的表达水平。进一步遗传学研究显示，巨噬细胞和中性粒细胞特异性敲除VCP的小鼠在白色念珠菌感染模型中表现出更高的易感性，这一结果也在使用VCP抑制剂的白色念珠菌感染小鼠模型中得到了验证。在机制方面，生化研究表明VCP与其辅助蛋白UFD1在Dectin-1受体激活后与SYK及其负调控因子SHP-1结合，形成复合体。本研究还发现SHP-1在Dectin-1激活后发生泛素化修饰，VCP或UFD1通过促进SHP-1的降解，从而有效地激活SYK和Dectin-1信号的转导。图例：模式图综上，本研究的结果首次证实了VCP能够显著促进Dectin-1信号通路的活化，并将VCP与Dectin-1通路及SYK的激活直接联系起来，进一步阐明了VCP在宿主抗真菌免疫防御中的关键作用。上述结果为理解Dectin-1信号通路活化的调控机制提供了新的视角，还为抗真菌免疫干预的潜在靶点提供了重要依据。论文链接： https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012674 原文链接： http://www.ips.ac.cn/tpxw/202412/t20241218_7503067.html 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

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