更新于：2024-09-19

UBA5

更新于：2024-09-19

基本信息

别名

FLJ23251、ThiFP1、UBA5

+ [6]

简介

E1-like enzyme which specifically catalyzes the first step in ufmylation (PubMed:15071506, PubMed:18442052, PubMed:25219498, PubMed:20368332, PubMed:27653677, PubMed:26929408, PubMed:27545674, PubMed:30412706, PubMed:27545681). Activates UFM1 by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a UFM1-E1 thioester and free AMP (PubMed:20368332, PubMed:27653677, PubMed:26929408, PubMed:30412706). Activates UFM1 via a trans-binding mechanism, in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer (PubMed:27653677). Trans-binding also promotes stabilization of the UBA5 homodimer, and enhances ATP-binding (PubMed:29295865). Transfer of UFM1 from UBA5 to the E2-like enzyme UFC1 also takes place using a trans mechanism (PubMed:27653677). Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress (PubMed:32160526). Ufmylation is essential for erythroid differentiation of both megakaryocytes and erythrocytes (By similarity).

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100 项与 UBA5 相关的临床结果

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100 项与 UBA5 相关的转化医学

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0 项与 UBA5 相关的专利（医药）

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项与 UBA5 相关的文献（医药）

2024-09-01·Autophagy

VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy

Article

作者: Wang, Xingde ; Xiong, Shuhui ; Wu, Zhaoyi ; Gong, Yamin ; Xu, Xingzhi ; Zhu, Wei-Guo ; Wang, Zhifeng

Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, which is regulated by factor BECN1 (beclin 1). UFMylation is a novel ubiquitin-like modification that has been demonstrated to modulate several cellular activities. However, the role of UFMylation in regulating autophagy has not been fully elucidated. Here, we found that VCP/p97 is UFMylated on K109 by the E3 UFL1 (UFM1 specific ligase 1) and this modification promotes BECN1 stabilization and assembly of the PtdIns3K complex, suggesting a role for VCP/p97 UFMylation in autophagy initiation. Mechanistically, VCP/p97 UFMylation stabilizes BECN1 through ATXN3 (ataxin 3)-mediated deubiquitination. As a key component of the PtdIns3K complex, stabilized BECN1 facilitates assembly of this complex. Re-expression of VCP/p97, but not the UFMylation-defective mutant, rescued the VCP/p97 depletion-induced increase in MAP1LC3B/LC3B protein expression. We also showed that several pathogenic VCP/p97 mutations identified in a variety of neurological disorders and cancers were associated with reduced UFMylation, thus implicating VCP/p97 UFMylation as a potential therapeutic target for these diseases. Abbreviation: ATG14:autophagy related 14; Baf A₁:bafilomycin A₁;CMT2Y: Charcot-Marie-Toothdisease, axonal, 2Y; CYB5R3: cytochromeb5 reductase 3; DDRGK1: DDRGK domain containing 1; DMEM:Dulbecco'smodified Eagle's medium;ER:endoplasmic reticulum; FBS:fetalbovine serum;FTDALS6:frontotemporaldementia and/or amyotrophic lateral sclerosis 6; IBMPFD1:inclusion bodymyopathy with early-onset Paget disease with or withoutfrontotemporal dementia 1; LC-MS/MS:liquid chromatography tandem mass spectrometry; MAP1LC3B/LC3B:microtubule associated protein 1 light chain 3 beta; MS: massspectrometry; NPLOC4: NPL4 homolog, ubiquitin recognition factor;PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3;PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K:phosphatidylinositol 3-kinase; RPL26: ribosomal protein L26; RPN1:ribophorin I; SQSTM1/p62: sequestosome 1; UBA5: ubiquitin likemodifier activating enzyme 5; UFC1: ubiquitin-fold modifierconjugating enzyme 1; UFD1: ubiquitin recognition factor in ERassociated degradation 1; UFL1: UFM1 specific ligase 1; UFM1:ubiquitin fold modifier 1; UFSP2: UFM1 specific peptidase 2; UVRAG:UV radiation resistance associated; VCP/p97: valosin containingprotein; WT: wild-type.

2024-07-01·Experimental Cell Research

UBA5 inhibition restricts lung adenocarcinoma via blocking macrophage M2 polarization and cisplatin resistance

Article

作者: Zhang, Chong ; Wei, Wenlu ; Xu, Dacai ; Zhang, Donghui

UBA5, a ubiquitin-like activated enzyme involved in ufmylation and sumoylation, presents a viable target for pancreatic and breast cancer treatments, yet its role in lung adenocarcinoma (LUAD) remains underexplored. This study reveals UBA5's tumor-promoting effect in LUAD, as evidenced by its upregulation in patients and positive correlation with TNM stages. Elevated UBA5 levels predict poor outcomes for these patients. Pharmacological inhibition of UBA5 using DKM 2-93 significantly curtails the growth of A549, H1299, and cisplatin-resistant A549 (A549/DDP) LUAD cells in vitro. Additionally, UBA5 knockdown via shRNA lentivirus suppresses tumor growth both in vitro and in vivo. High UBA5 expression adversely alters the tumor immune microenvironment, affecting immunostimulators, MHC molecules, chemokines, receptors, and immune cell infiltration. Notably, UBA5 expression correlates positively with M2 macrophage infiltration, the predominant immune cells in LUAD. Co-culture experiments further demonstrate that UBA5 knockdown directly inhibits M2 macrophage polarization and lactate production in LUAD. Moreover, in vivo studies show reduced M2 macrophage infiltration following UBA5 knockdown. UBA5 expression is also associated with increased tumor heterogeneity, including tumor mutational burden, microsatellite instability, neoantigen presence, and homologous recombination deficiency. Experiments indicate that UBA5 overexpression promotes cisplatin resistance in vitro, whereas UBA5 inhibition enhances cisplatin sensitivity in both in vitro and in vivo settings. Overall, these findings suggest that targeting UBA5 inhibits LUAD by impeding cancer cell proliferation, M2 macrophage polarization, and cisplatin resistance.

2024-07-01·Archives of Insect Biochemistry and Physiology

Bombyx mori UFL1 facilitates BmNPV proliferation by regulating host cell apoptosis through PERK

Article

作者: Meng, Haonan ; Huang, Shoujun ; Jiang, Xiaochun ; Zheng, Yijun

AbstractUbiquitin‐fold modifier 1 (UFM1) is attached to protein substrates through the sequential activity of an E1 (UBA5)‐E2 (UFC1)‐E3 (UFL1) cascade. UFL1 is the E3 ligase for UFMylation in vertebrates. However, there have been no studies on UFL1 in silkworm to date. In this study, we identified a UFL1 ortholog in Bombyx mori genome. Spatio‐temporal expression profiles showed that BmUFL1 expression was high in the midgut, epidermis, and testis and in the pupa–adult stage. BmUFL1 knockdown inhibited B. mori nucleopolyhedrovirus (BmNPV) proliferation, while BmUFL1 overexpression promoted BmNPV proliferation. Mechanically, protein kinase RNA‐like endoplasmic reticulum kinase (PERK) signaling and cell apoptosis are involved in BmUFL1‐regulated BmNPV proliferation. Overall, these results suggest that BmUFL1 facilitates BmNPV proliferation in silkworm.

项与 UBA5 相关的新闻（医药）

2024-03-05

·今日头条

再取进展！张金方课题组揭示“PD-1”调控新机制及其在肿瘤免疫逃逸和治疗中的作用

本文为转化医学网原创，转载请注明出处作者：Sophia 导读： UFMylation 是一种新兴的泛素样翻译后修饰，可调节各种生物过程。UFMylation 通路的失调会引发各种人类疾病，包括癌症。然而，UFMylation在T细胞中的生理作用仍不清楚。近日，武汉大学医学研究院、教育部免疫与代谢前沿科学中心、中南医院以及泰康生命医学中心张金方课题组在《Molecular Cell》杂志上发表了题为“UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity”的论文。研究揭示了靶向AMPK-UFL1-PD-1信号轴能够增强抗肿瘤免疫，为临床癌症患者提供了潜在的治疗策略。 https://www-sciencedirect-com.libproxy1.nus.edu.sg/science/article/abs/pii/S1097276524000911 研究背景 01 UFMylation 是一种新兴的泛素样（UBL）修饰系统，它利用涉及 E1（泛素激活酶 5、UBA5）、E2（UFM1-共轭酶 1、UFC1）和 E3（UFM1-连接酶 1、UFL1，也称为 RCAD、KIAA0776、NLBP 或 MAXER）的三酶级联反应，将泛素折叠修饰物 1 （UFM1）共价偶联到靶向蛋白质。与对泛素化功能的广泛研究相比，UFM化作用的生理作用探索较少。目前，只有 UFL1 被鉴定为 UFMylation E3 连接酶。UFL1介导的UFM化在调节胚胎发育、内质网（ER）稳态和内质网自噬、DNA损伤反应和病毒感染后干扰素反应中的功能重要性得到了强调。尽管在癌症中已经报道了异常的UFM化，但这些研究主要集中在了解UFMylation的肿瘤内在功能上，UFMylation在肿瘤发生中发挥着矛盾的作用，这取决于不同的癌症类型。尽管 T 细胞在控制肿瘤生长和基于 T 细胞的癌症免疫疗法中起着至关重要的作用，但 T 细胞中 UFMylation 和 T 细胞介导的抗肿瘤免疫的潜在功能仍未得到探索。免疫细胞，尤其是效应CD8+T淋巴细胞，可以通过抗原定向的细胞毒性来识别和消除癌细胞，强调了免疫系统在对抗癌症中的重要性。然而，由于肿瘤微环境（TME）中的 T 细胞功能障碍，肿瘤浸润淋巴细胞（TIL）通常无法有效杀死癌细胞。T细胞上上调抑制性免疫检查点受体，如程序性细胞死亡蛋白1（PD-1，也称为PDCD1或CD279）和细胞毒性T淋巴细胞抗原-4（CTLA-4，也称为CD152）是抑制T细胞活化和细胞毒性的机制之一。因此，靶向PD-1和CTLA-4的基于T细胞的免疫疗法已广泛应用于癌症患者的临床治疗。然而，大多数患者对这些免疫疗法没有反应，潜在的耐药机制仍不完全清楚。最近对 PD-1/PD-L1 蛋白表达调控的研究确定了增强抗癌功效的新的潜在治疗策略。多项研究表明，PD-1 蛋白可以通过泛素 E3 连接酶进行泛素化修饰，从而通过蛋白酶体系统降解 PD-1。因此，操纵PD-1的泛素化状态可以控制T细胞中PD-1蛋白的表达水平，从而影响T细胞的细胞毒性功能。研究结果 02 本研究，我们发现与野生型小鼠相比，在T细胞中条件性敲除Ufl1的小鼠（Ufl1cKO）表现出显著的肿瘤抑制现象。此外，单细胞测序数据显示来自Ufl1cKO小鼠的肿瘤，其浸润性细胞毒性CD8+T细胞显著增加。进一步研究表明UFL1能够与PD-1产生直接的相互作用并促进PD-1的UFMylation修饰，以拮抗PD-1的泛素化修饰和降解。而且，我们还发现感受能量代谢的激酶AMPK能够催化UFL1蛋白Thr536位点发生磷酸化修饰，14-3-3γ可以识别AMPK介导的UFL1的磷酸化修饰，破坏UFL1与PD-1的相互作用，导致PD-1不稳定，从而增强CD8+T细胞抗肿瘤免疫。值得注意的是，研究人员不仅证明Ufl1cKO小鼠对CTLA4抗体治疗有更好的响应，还发现使用AMPK激动剂和CTLA-4抗体联合治疗时具有协同抑制肿瘤生长的效果。综上所述，该研究揭示了靶向AMPK-UFL1-PD-1信号轴能够增强抗肿瘤免疫，为临床癌症患者提供了潜在的治疗策略。参考资料： https://news.whu.edu.cn/info/1015/453047.htm https://www-sciencedirect-com.libproxy1.nus.edu.sg/science/article/abs/pii/S1097276524000911 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。

免疫疗法细胞疗法蛋白降解靶向嵌合体

2024-02-22

·奇点网

又一种影响PD-1的机制出现了~

*仅供医学专业人士阅读参考抗癌免疫看T细胞，T细胞是否给力又看PD-1/L1通路，而作为一种蛋白质，PD-1的“状态”则会受到蛋白质翻译后修饰（PTMs）的显著影响[1]。所以找到并针对关键的翻译后修饰过程，同样有可能深远地影响T细胞主导的抗肿瘤免疫应答。近日，武汉大学医学研究院张金方团队与台北中央研究院生物医学科学研究所李育儒团队及其他国内外学者合作，在Molecular Cell期刊发表的最新研究成果，就揭示了调控T细胞PD-1蛋白UFMylation修饰的关键靶点UFL1：UFL1的存在可拮抗PD-1泛素化修饰和降解，将其敲除则可更好地激活CD8+T细胞，因此UFL1有望成为新的免疫治疗靶点[2]。论文核心内容总结对不熟悉表观遗传领域的读者来说，UFMylation修饰可能是个非常新颖的词，那奇点糕就先说明一下，它也是近年来被发现的类泛素化（ubiquitin-like）修饰之一，可能参与了胚胎发育、内质网稳态、DNA损伤修复等许多生理进程[3]，但相关研究还依然在起步阶段，UFL1则是目前唯一被证实参与UFMylation修饰的E3连接酶。至于UFMylation修饰对T细胞和PD-1/L1通路，乃至癌症免疫治疗的影响，还都笼罩在迷雾之中呢，所以本次研究就算是拨开迷雾的第一步。研究者们首先条件性敲除了小鼠T细胞中的Ufl1基因，发现与野生型小鼠相比，敲除Ufl1后小鼠生理状态和T细胞发育仍保持稳定，且植入的小鼠肺癌（LLC细胞）和结直肠癌细胞（MC38细胞）都遭遇了有力的抑制。对小鼠肿瘤微环境内免疫细胞进行的单细胞测序则显示，敲除Ufl1基因小鼠肿瘤内的细胞毒性CD8+效应T细胞、CD4+T细胞等T细胞亚群浸润显著更多，而耗竭CD8+T细胞较野生型小鼠显著减少，转录组学分析也发现了多种T细胞激活和效应相关的分子标志物（如CD69、TNF）表达上调，基因通路富集分析则提示了免疫相关通路的明确活跃。敲除Ufl1可正向影响抗肿瘤免疫应答的多个方面这些结果意味着敲除Ufl1使CD8+T细胞整体在抗癌中更为活跃了，且UFL1对抗肿瘤免疫应答的正向作用明确依赖于CD8+T细胞，那接下来的探索方向，就是找到UFL1对CD8+T细胞施加正向影响的机制，而研究者们首先想到的就是PD-1/L1等免疫检查点通路。蛋白免疫印迹和流式分选（FACS）分析证实，PD-1是敲除Ufl1后，CD8+T细胞唯一发生表达显著下调的已知免疫检查点分子，且单细胞测序中并未发现PD-1 mRNA水平的下调，说明敲除Ufl1对PD-1表达的影响很可能发生在翻译后修饰环节，这就对上了UFL1参与UFMylation修饰的正常生理功能。进一步实验证实，敲除Ufl1或敲除/抑制参与UFMylation修饰的其它酶（如UBA5等），均可显著下调CD8+T细胞内的PD-1蛋白水平，进而影响CD8+T细胞的激活状态，而且从T细胞激活到耗竭的全过程中，UFL1都可直接与PD-1蛋白发生相互作用，介导UFMylation修饰以拮抗PD-1的泛素化修饰（K48位点）和降解，对稳定PD-1蛋白水平起到重要作用。UFL1介导的UFMylation修饰可稳定PD-1蛋白水平而大名鼎鼎的AMPK激酶，则会通过磷酸化UFL1蛋白T536位点，使UF1无法与桥梁蛋白14-3-3γ发生正常的相互作用，直接干扰UFL1参与UFMylation修饰的功能，从而使AMPK激酶成为调控UFL1的上游分子，即存在AMPK-UFL1-PD-1的调控轴。最后，研究者们分析了敲除Ufl1对现有免疫治疗的影响：敲除Ufl1可使小鼠对CTLA-4抑制剂治疗的应答更好，这要归功于CD8+T细胞的激活状态改善，在此基础上联合AMPK激动剂可以进一步增效；但由于敲除Ufl1使PD-1蛋白减少，相当于已起到了抑制PD-1的作用，PD-1抑制剂的疗效并未同样显著增强，需要与CTLA-4抑制剂搭档使用才行。敲除Ufl1可增敏CTLA-4抑制剂总之，本次研究率先揭示了UFL1参与的UFMylation修饰对T细胞抗肿瘤免疫能力的重要影响，不过这还只是解谜的第一步，因为近期也有研究显示，PD-1的配体PD-L1同样会受到UFMylation修饰调控，UFL1和UFMylation修饰在免疫细胞/癌细胞中影响究竟如何，怎样实现对AMPK-UFL1-PD-1信号轴的精准干预，都还是悬而未决、值得探索的问题。参考文献：[1]Lee T A, Tsai E Y, Liu S H, et al. Post-translational Modification of PD-1: Potential Pathways for Cancer Immunotherapy[J]. Cancer Research, 2024.[2]He C, Xing X, Chen H Y, et al. UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity[J]. Molecular Cell, 2024.[3]Zhou X, Mahdizadeh S J, Le Gallo M, et al. UFMylation: a ubiquitin-like modification[J]. Trends in Biochemical Sciences, 2024, 49(1): 52-67.本文作者丨谭硕

免疫疗法细胞疗法