UFM1

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。

Researchers reveal how cells regenerate protein factories at endoplasmic reticulum. Researchers at LMU and Stanford University reveal how cells regenerate protein factories at endoplasmic reticulum. The synthesis of proteins in the cell is a key process of life. By this means, the genetic code of the genome is translated into the amino acid sequence of proteins. The process is complex -- and has been studied in detail for decades. Protein biosynthesis is performed by special molecular machines, ribosomes, which consist of a large and small subunit. At the end of protein biosynthesis, these protein factories have to be broken up into their individual parts (recycled), so that they are ready for the next round of translation. Now a team led by Professor Roland Beckmann, Dr. Thomas Becker, and Ivan Penchev from LMU's Gene Center Munich, working in collaboration with researchers at Stanford University led by Professor Ron Kopito, have shown how the recycling of ribosomes at the so-called endoplasmic reticulum (ER) functions. In the process, they discovered the role of an enzyme, a special E3 ligase that joins a small protein modification called UFM1 to the large ribosomal subunit, as a key mechanism of recycling. An account of their investigations has been published in the journal Nature. Detailed insights into the recycling of ribosomes Ribosomes are usually found floating within the cytoplasm. "Here we know precisely how the recycling works," says Becker. Sometimes, however, they are located at the endoplasmic reticulum, a continuous cell-wide membrane network. Although many proteins originate in the cytosol, they subsequently have to be brought to other organelles, such as mitochondria, chloroplasts, and many more. If a protein is synthesized at the ER membrane, the whole translation machinery docks to the ER membrane. This is accomplished with the aid of a protein-conducting channel (SEC61), which is able to transport proteins across the membrane or insert them into the membrane during synthesis. After completion of the translation, there is a further recycling step, which is specific to the ER membrane. Namely, the large subunit of the ribosome has to be detached again from the protein-conducting channel. Beckmann's team has now demonstrated how this substep works: When the translation has finished, the E3 ligase recognizes the large subunit of the ribosomes. "It places -- figuratively speaking -- a small wedge, the protein UFM1, at the large subunit," explains Becker. "This produces a stable complex out of the modified 60S subunit and the E3 ligase. Simultaneously, it causes the large subunit to detach from SEC61. This is a very important step to ensure that the large subunit is returned to the cytosol and available for the next round."