更新于：2024-05-01

UFL1

UFM1 specific ligase 1

更新于：2024-05-01

基本信息

别名

E3 UFM1-protein ligase 1、E3 UFM1-protein transferase 1、KIAA0776

+ [8]

简介

E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins, and which plays a key role in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress (PubMed:20018847, PubMed:20164180, PubMed:20228063, PubMed:25219498, PubMed:32160526). In response to endoplasmic reticulum stress, recruited to the endoplasmic reticulum membrane by DDRGK1, and mediates ufmylation of proteins such as RPN1 and RPL26/uL24, thereby promoting reticulophagy of endoplasmic reticulum sheets (PubMed:32160526). Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) via ERN1/IRE1-alpha (PubMed:23152784, PubMed:32160526). Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response (PubMed:32050156). Regulates inflammation in response to endoplasmic reticulum stress by promoting reticulophagy, leading to inhibit the activity of the NF-kappa-B transcription factor (By similarity). Mediates ufmylation of DDRGK1 and CDK5RAP3; the role of these modifications is however unclear: as both DDRGK1 and CDK5RAP3 act as substrate adapters for ufmylation, it is uncertain whether ufmylation of these proteins is a collateral effect or is required for ufmylation (PubMed:20531390, PubMed:20018847). Catalyzes ufmylation of various subunits of the ribosomal complex or associated components, such as RPS3/uS3, RPS20/uS10, RPL10/uL16, RPL26/uL24 and EIF6 (By similarity). Anchors CDK5RAP3 in the cytoplasm, preventing its translocation to the nucleus which allows expression of the CCND1 cyclin and progression of cells through the G1/S transition (PubMed:20531390). Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4 (PubMed:30886146). Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription (PubMed:25219498). Required for hematopoietic stem cell function and hematopoiesis (By similarity). Required for cardiac homeostasis (By similarity).

关联

100 项与 UFL1 相关的临床结果

登录后查看更多信息

100 项与 UFL1 相关的转化医学

登录后查看更多信息

0 项与 UFL1 相关的专利（医药）

登录后查看更多信息

项与 UFL1 相关的文献（医药）

2024-02-21·Nature

The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.

Article

作者: Linda Makhlouf ; Joshua J Peter ; Helge M Magnussen ; Rohan Thakur ; David Millrine ; Thomas C Minshull ; Grace Harrison ; Joby Varghese ; Frederic Lamoliatte ; Martina Foglizzo ; Thomas Macartney ; Antonio N Calabrese ; Elton Zeqiraj ; Yogesh Kulathu

Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26 (also known as uL24)^1,2. This modification, which is known as UFMylation, is orchestrated by the UFM1 ribosome E3 ligase (UREL) complex, comprising UFL1, UFBP1 and CDK5RAP3 (ref. ³). However, the catalytic mechanism of UREL and the functional consequences of UFMylation are unclear. Here we present cryo-electron microscopy structures of UREL bound to 60S ribosomes, revealing the basis of its substrate specificity. UREL wraps around the 60S subunit to form a C-shaped clamp architecture that blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other. A UFL1 loop inserts into and remodels the peptidyl transferase centre. These features of UREL suggest a crucial function for UFMylation in the release and recycling of stalled or terminated ribosomes from the ER membrane. In the absence of functional UREL, 60S-SEC61 translocon complexes accumulate at the ER membrane, demonstrating that UFMylation is necessary for releasing SEC61 from 60S subunits. Notably, this release is facilitated by a functional switch of UREL from a 'writer' to a 'reader' module that recognizes its product-UFMylated 60S ribosomes. Collectively, we identify a fundamental role for UREL in dissociating 60S subunits from the SEC61 translocon and the basis for UFMylation in regulating protein homeostasis at the ER.

2024-02-21·Nature

UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.

Article

作者: Paul A DaRosa ; Ivan Penchev ; Samantha C Gumbin ; Francesco Scavone ; Magda Wąchalska ; Joao A Paulo ; Alban Ordureau ; Joshua J Peter ; Yogesh Kulathu ; J Wade Harper ; Thomas Becker ; Roland Beckmann ; Ron R Kopito

Reversible modification of target proteins by ubiquitin and ubiquitin-like proteins (UBLs) is widely used by eukaryotic cells to control protein fate and cell behaviour¹. UFM1 is a UBL that predominantly modifies a single lysine residue on a single ribosomal protein, uL24 (also called RPL26), on ribosomes at the cytoplasmic surface of the endoplasmic reticulum (ER)^2,3. UFM1 conjugation (UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are released after ribosome-associated quality-control-mediated splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER^3,4. Neither the molecular mechanism by which the UFMylation machinery achieves such precise target selection nor how this ribosomal modification promotes 60S rescue is known. Here we show that ribosome UFMylation in vivo occurs on free 60S and we present sequential cryo-electron microscopy snapshots of the heterotrimeric UFM1 E3 ligase (E3(UFM1)) engaging its substrate uL24. E3(UFM1) binds the L1 stalk, empty transfer RNA-binding sites and the peptidyl transferase centre through carboxy-terminal domains of UFL1, which results in uL24 modification more than 150 Å away. After catalysing UFM1 transfer, E3(UFM1) remains stably bound to its product, UFMylated 60S, forming a C-shaped clamp that extends all the way around the 60S from the transfer RNA-binding sites to the polypeptide tunnel exit. Our structural and biochemical analyses suggest a role for E3(UFM1) in post-termination release and recycling of the large ribosomal subunit from the ER membrane.

2024-02-09·Molecular cell

UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity.

Article

作者: Chuan He ; Xixin Xing ; Hsin-Yi Chen ; Minling Gao ; Jie Shi ; Bolin Xiang ; Xiangling Xiao ; Yishuang Sun ; Haisheng Yu ; Gaoshan Xu ; Yingmeng Yao ; Zuosong Xie ; Yujie Xing ; Bugi Ratno Budiarto ; Shih-Yu Chen ; Yang Gao ; Yu-Ru Lee ; Jinfang Zhang

UFMylation is an emerging ubiquitin-like post-translational modification that regulates various biological processes. Dysregulation of the UFMylation pathway leads to human diseases, including cancers. However, the physiological role of UFMylation in T cells remains unclear. Here, we report that mice with conditional knockout (cKO) Ufl1, a UFMylation E3 ligase, in T cells exhibit effective tumor control. Single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8⁺ T cells are increased in Ufl1 cKO mice. Mechanistically, UFL1 promotes PD-1 UFMylation to antagonize PD-1 ubiquitination and degradation. Furthermore, AMPK phosphorylates UFL1 at Thr536, disrupting PD-1 UFMylation to trigger its degradation. Of note, UFL1 ablation in T cells reduces PD-1 UFMylation, subsequently destabilizing PD-1 and enhancing CD8⁺ T cell activation. Thus, Ufl1 cKO mice bearing tumors have a better response to anti-CTLA-4 immunotherapy. Collectively, our findings uncover a crucial role of UFMylation in T cells and highlight UFL1 as a potential target for cancer treatment.

项与 UFL1 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

2023-06-21

·生物谷

中国药科大学研究者们揭示了核糖体蛋白L10在胰腺癌发生发展中的作用

胰腺癌(PAAD)是一种治疗手段最少的实体恶性肿瘤，其五年存活率仅为9%。因为大多数患者被发现处于晚期，他们自动错过了最好的治疗机会。胰腺癌(PAAD)是一种治疗手段最少的实体恶性肿瘤，其五年存活率仅为9%。因为大多数患者被发现处于晚期，他们自动错过了最好的治疗机会。虽然手术和辅助化疗是治疗PAAD的常用方法，但这些治疗方法通常不能达到预期的治疗效果。吉西他滨是治疗局部晚期和转移性PAAD的标准疗法，不能为PAAD患者提供满意的益处，在几周内就会出现明显的化疗耐药。同时，与吉西他滨单独治疗相比，吉西他滨联合治疗的改善也有限。因此，迫切需要新的治疗策略来改善PAAD的预后。图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-05877-y 近日，来自中国药科大学的研究者们在Cell Death and Disease杂志上发表了题为“The ufmylation modification of ribosomal protein L10 in the development of pancreatic adenocarcinoma”的文章，该研究综述了核糖体蛋白L10非甲基化修饰在胰腺癌发生发展中的作用。胰腺癌(PAAD)是恶性程度最高、死亡率最高的癌症。尽管核糖体蛋白L10(RPL10)与PAAD相关，以及RPL26超甲基化的报道，但RPL10超甲基化与PAAD发生的关系尚不清楚。在本研究中，我们总结了RPL10的超甲基化过程的解剖以及RPL10在PAAD发展中的潜在作用。在胰腺患者组织和细胞系中都证实了RPL10的超甲基化，并鉴定和验证了特定的修饰位点。表型上，RPL10超甲基化显著增加了细胞的增殖和干性，这主要是由于转录因子KLF4的高表达所致。此外，RPL10中超甲基化位点的突变进一步证明了RPL10中超甲基化与细胞增殖和干性的关系。综上所述，这项研究揭示了PRL10的ufm化在增强胰腺癌细胞的干性方面对PAAD的发展起着重要的作用。证实UFl1参与体内肿瘤发生和细胞干细胞分化图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-05877-y 综上所述，本研究已经证实RPL10在胰腺癌细胞、移植瘤组织以及PAAD患者的肿瘤组织中存在超甲基化。RPL10超甲基化已被证明与细胞干性和PAAD的发生有关。因此，干扰RPL10超甲基化可能代表了PAAD的一种新的治疗策略。这项研究不仅为RPL10的核糖体外功能提供了新的见解，也为PAAD的潜在治疗提供了线索。（生物谷 Bioon.com）参考文献 Kun Wang et al. The ufmylation modification of ribosomal protein L10 in the development of pancreatic adenocarcinoma. Cell Death Dis. 2023 Jun 7;14(6):350. doi: 10.1038/s41419-023-05877-y.