UBC12

引言UBE2F是一种类化E2，通过与拟素化修饰E3 RBX2/SAG偶联，使CUL5类化激活cullin-RING连接酶。UBE2F是否以及如何控制胰腺肿瘤发生以前是未知的。2024年4月3日，浙江大学孙毅团队在Developmental Cell 在线发表题为“The UBE2F-CRL5ASB11-DIRAS2 axis is an oncogene and tumor suppressor cascade in pancreatic cancer cells”的研究论文，该研究发现UBE2F对于KRAS突变的人胰腺癌细胞的生长是必不可少的。在小鼠KrasG12D胰腺导管腺癌(PDAC)模型中，Ube2f缺失抑制了蓝蛋白诱导的胰腺炎，以及腺泡到导管化生(ADM)和胰腺上皮内瘤变的进展。从机制上讲，Ube2f缺失通过阻断Diras2 (CRL5ASB11 E3连接酶的底物)的泛素化使Mapk-c-Myc信号失活。生物学上，DIRAS2抑制了携带突变KRAS的人胰腺癌细胞的生长和存活，而DIRAS2缺失在很大程度上挽救了Ube2f缺失诱导的表型。综上所述，Ube2f和Diras2在小鼠KrasG12D PDAC模型中分别发挥肿瘤促进或肿瘤抑制作用。UBE2F-CRL5ASB11轴可以作为胰腺癌的有效靶标，而UBE2F或DIRAS2的水平可以作为PDAC患者的预后生物标志物。胰腺导管腺癌(Pancreatic ductal adencarcinoma, PDAC)分别是美国和中国癌症死亡的第四大或第五大原因，是最致命的人类恶性肿瘤之一，5年生存率仅为3%-5%，主要原因是诊断较晚和有效治疗有限。慢性胰腺炎是PDAC发生的重要危险因素，在胰腺炎期间，炎症触发腺泡细胞的部分去分化，以获得导管上皮的身份，这种转化被称为腺泡到导管化生(ADM)。在小鼠胰腺上皮内瘤变(mPanIN)形成和PDAC肿瘤形成之前，在小鼠KrasG12D PDAC模型中重现，当胰腺炎诱导时，mPanIN的形成加速。泛素化修饰是一种可逆的翻译后修饰，将NEDD8(神经前体细胞-表达发育下调8)偶联到目标底物的赖氨酸残基上，由NAE (NEDD8激活酶)E1、两种E2中的一种UBE2M/UBC12(泛素偶联酶E2M)或UBE2F(泛素偶联酶E2F)以及几种E3连接酶之一催化。包括RBX1 (RING Box蛋白1)和SAG(凋亡敏感基因)/RBX2 (RING Box蛋白2)。cullin-RING连接酶(CRL)的Cullin亚基是最具特征的生理底物Cullin类泛素化是激活CRLs的必要条件，主要包括CRLs、CRL4A、CRL4B和CRL5，它们通过泛素-蛋白体系统(Ubiquitin-Proteosome System, UPS)使约20%的细胞蛋白泛素化并降解。ube2fe2与E3 SAG/RBX2偶联可类化Cul5并激活CRL5, CRL5由支架Cul5、接头蛋白伸长蛋白B/C、环蛋白SAG/RBX2和底物泛素化和降解的底物结合亚基组成另一方面，UBE2M E2与RBX1偶联，对cullins 1-4进行拟素化，并激活CRLs1-4，使其泛素化并降解许多底物。由于NEDD8和拟素化修饰E2和E3酶的过度表达，拟素化通路在多种人类癌症中被过度激活，更重要的是，拟素化修饰途径的过度激活与癌症患者的不良生存呈正相关。前期研究表明，在肺癌中，NEDD8、NAE1、UBE2M/UBC12、UBE2F、和SAG/RBX2过表达，与癌症患者生存不良相关。在胰腺癌中，NEDD8、NAE1、SAG过表达与患者生存不良呈正相关。此外，最近使用胰腺特异性SAG转基因和敲除小鼠模型的研究表明，SAG是KrasG12D诱导的PDAC发展所必需的。尽管有报道称UBE2F在几种癌症中发挥促进生长的作用，但UBE2F是否以及如何在体外调节KRAS突变的胰腺癌细胞的生长和存活以及体内胰腺肿瘤的发生，此前尚不清楚。模式图（Credit: Developmental Cell）DIRAS2是DIRAS家族中一个研究较少的成员，该家族有三个成员，与促癌RAS GTPasas具有30%-40%的氨基酸同源性与大多数致癌RAS家族基因不同，DIRAS家族成员具有低水平的GTPase活性，并且主要以GTP结合形式存在。它们不能与RAF的RAS结合域相互作用，也不能刺激丝裂原活化蛋白激酶(MAPK)。最近的一项研究表明，DIRAS3直接结合RAS并破坏RAS簇以阻断RAS/ MAPK信号。然而，DIRAS2是否以及如何调节KRAS突变或KrasG12D诱导的胰腺肿瘤发生的胰腺癌细胞的生长和存活尚不清楚。此外，在KRAS突变的胰腺癌细胞中，E3连接酶如何调节DIRAS2的稳定性仍然是未知的。该研究报道了UBE2F在体外促进KRAS突变的胰腺癌细胞的生长和存活，以及体内从ADM到mPanINs的肿瘤进展。在机制上，UBE2F与SAG/RBX2偶联以拟素化Cul5激活CRL5，从而泛素化并降解DIRAS2。该研究将ASB11定性为CRL5的底物受体，使DIRAS2失活。重要的是，该研究发现在KrasG12D PDAC模型中，Ube2f缺失引起了Diras2的积累，从而抑制了肿瘤的进展，而Diras2缺失则促进了这一过程，并恢复了Ube2f缺失的抑制作用，表明了Diras2的因果作用。最后，还发现在胰腺癌组织中，高UBE2F和低DIRAS2水平与较差的患者生存率相关。因此，该研究验证了UBE2F-CRL5ASB11是KRAS突变PDAC的一个有吸引力的药物靶点。原文链接https://doi.org/10.1016/j.devcel.2024.03.018责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

Insightful data comes from collaborations with Stanford University, University of Tennessee, Oak Ridge National Laboratory, and leading hospitals in Mexico across various stages of development BOSTON--(BUSINESS WIRE)-- BPGbio, Inc., a leading biology-first AI-powered biopharma that focuses on oncology, neurology, and rare diseases, today announced the application of its NAi Interrogative Biology® Platform across several drug and diagnostic applications, following successful collaborations with Stanford University, University of Tennessee, Oak Ridge National Laboratory, and several leading hospitals across Mexico. The company will present four posters showcasing these research collaborations and provide updates on other internal research activities at the American Association for Cancer Research (AACR) Annual Meeting being held April 5-10, 2024, in San Diego, Calif. This press release features multimedia. View the full release here: A graphical representation of BPGbio's NAi Interrogative Biology Platform (Graphic: Business Wire) Highlights from posters include: New data further validating the mitochondrial-centric effect of BPM31510 on the immune system. In addition to its direct cell-killing effect on tumor cells, data supports the potential use of BPM31510 in the intersection of tumor immunology and tumor metabolism BPGbio’s NAi Platform coupled with a subsequent deep learning algorithm implemented on BRG399, a novel pan-cancer drug candidate, can improve efficiency in drug development by rapidly predicting anti-cancer efficacy in silico before conducting resource intensive preclinical experiments A new study in Mexico further validating the utility of BPGbio’s prostate cancer biomarker, the pstateDx™ test, which was discovered by the NAi Platform, in an independent population New data validating UBE2M, a novel potential therapeutic target for cancer, identified by the NAi Platform. “Our company has pioneered and proliferated a unique biology-first approach to the use of AI in drug discovery and development as we focus on high unmet disease indications,” said Niven R. Narain, Ph.D., President and CEO, BPGbio, Inc. “Our NAi Interrogative Biology platform has guided our development team via many successful research collaborations enabling us to deliver positive clinical trial readouts across multiple indications in various stages of development. Our goal is to offer potential and hope to patients and families facing ravaging diseases like GBM and pancreatic cancer.” Presentation Details: Abstract 3527: Application of deep learning-based drug sensitivity prediction model on a novel anticancer drug Presentation: Monday, April 8, 2024, 1:30-5:00 p.m. in Poster Section 35 Abstract 3751: Diagnostic assessment of Filamin A (FLNA) as a serum biomarker for identification of benign prostatic hyperplasia vs. aggressive prostate cancer in a prospective Mexican cohort Presentation: Monday, April 8, 2024, 1:30 - 5:00 p.m. in Poster Section 44 Abstract 4694: In charge: Targeting neddylation of UBE2M for anticancer therapy Presentation: Tuesday, April 9, 2024, 9:00 a.m. - 12:30 p.m. in Poster Section 28 Abstract 6518: BPM31510: Targeting the tumor microenvironment (TME) via mitochondrial-mediated ROS production Presentation: Tuesday, April 9, 2024, 1:30 - 5:00 p.m. in Poster Section 47 About the NAi Interrogative Biology Platform The NAi Interrogative Biology Platform combines BPGbio’s industry-leading, clinically annotated proprietary biobank, purpose-built Bayesian artificial intelligence, and the compute power of the world’s fastest supercomputer, Frontier, housed at Oak Ridge National Laboratory. Collectively, these tools enable the company to bring artificial intelligence to biology inspiring AI-driven target nomination, discovery, molecule design, and more. The platform has been used to identify more than 100 drug targets and diagnostic biomarkers and supported research collaborations with a range of government, industry and academic partners including the U.S. Department of Defense, Sanofi, and Harvard Medical School. About BPM31510 BPM31510 is BPGbio’s lead candidate in late-stage development for glioblastoma multiforme (GBM) and pancreatic cancer. The compound has demonstrated a tolerable safety pro shown potential clinical benefit in both populations. The mechanism of action of BPM31510 was first validated by data from BPGbio’s NAi Interrogative Biology platform, which suggested that there is a hallmark shift in the tumor microenvironment (TME) induced by BPM31510 which modulates mitochondrial oxidative phosphorylation in highly aggressive tumors. About BRG399 BRG399, a BPGbio-developed oral experimental drug with favorable pharmacological properties for clinical testing, is a first in class anti-mitotic agent with broad-spectrum anti-cancer activity. BRG399 is being studied for its therapeutic potential as a treatment for solid and liquid tumor cancers as well as diseases associated with inflammation. BPGbio’s scientists reported that the anti-mitotic activity of BRG399 is the result of an inhibition of microtubule polymerization. About pstateDx™ ​​BPGbio’s pstateDx™ test is the first diagnostic product discovered by the company’s AI-powered NAi Interrogative Biology platform to be commercially launched. The pstateDx™ test is a non-PSA based, unique molecular diagnostic blood test that measures filamin A, a key biological driver of prostate cancer. The test provides a risk score to help clinicians differentiate between BPH and aggressive prostate cancer at the time of initial screening. It may help reduce unnecessary biopsies in the BPH population, where men are sometimes repeatedly biopsied even though they do not have prostate cancer. About BPGbio, Inc. BPGbio is a leading AI-powered clinical stage biopharma and diagnostics company focused on oncology, neurology, and rare diseases. The company has a deep portfolio of AI-developed pipeline of therapeutics, including several in late-stage development. BPGbio’s novel approach is underpinned by NAi, its proprietary Interrogative Biology Platform, protected by over 400 US and international patents; one of the world’s largest clinically annotated non-governmental biobanks; and exclusive access to the most powerful supercomputer in the world. With these tools, BPGbio is redefining how patient biology can be modeled using unbiased AI. Headquartered in Boston, the company is at the forefront of a new era in medicine, combining biology, data, and AI to transform the way we understand aging, human performance, and diagnose and treat disease. For more information, visit bpgbio.com

系统性红斑狼疮(SLE)是一种自身耐受性下降和自身抗体产生的多系统自身免疫性疾病。双阴性(CD3+CD4-CD8-，dN)T细胞是一种独特的缺乏CD4和CD8共同受体的T细胞亚群，在自身免疫性疾病(如SLE)的发病机制中起重要作用。此外，糖尿病肾病T细胞能够促进B细胞分化，促进自身抗体的产生。此外，糖尿病肾病T细胞产生大量干扰素-γ和IL-17，可促进系统性红斑狼疮的发生发展。因此，糖尿病肾病T细胞的动态平衡在狼疮发病机制中起关键作用。因此，阐明介导糖尿病肾病T细胞动态平衡的信号事件可能为SLE提供新的潜在治疗选择。图片来源：https://doi.org/10.1038/s41392-023-01709-9近日，来自浙江中医药大学的研究者们在Signal Transduction and Targeted Therapy杂志上发表了题为“Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis”的文章，该研究揭示了去甲肾上腺素通过调节双阴性T细胞稳态成为狼疮治疗的新靶点。系统性红斑狼疮(SLE)是一种严重的自身免疫性疾病，以全身炎症反应、自身抗体积聚和器官损害为特征。双阴性T细胞的异常调节被认为是SLE发病的重要因素。去甲基化是一种重要的蛋白质翻译后修饰(PTM)，已被证明可以调节T细胞介导的免疫反应。然而，肾病在系统性红斑狼疮中的作用仍不清楚。在本研究中，研究者报道了用NEDD8激活酶E1(NAE1)的特异性抑制剂MLN4924去氧灭活或遗传去除T细胞中的Ube2m，可减少DNT细胞的聚集，并减缓小鼠狼疮的发展。进一步的研究表明，去甲肾上腺素抑制了糖尿病肾病T细胞中Bim泛素化的降解，并维持了糖尿病肾病T细胞中的Bim水平，从而促进了狼疮小鼠累积的糖尿病肾病T细胞的凋亡。然后建立双基因敲除(KO)狼疮易感小鼠(Ube2m-/-Bim-/-LPR)，结果表明，Bim的缺失减少了Ube2m缺乏诱导的糖尿病肾病T细胞的凋亡，并逆转了狼疮的进展。本研究结果表明，去甲肾上腺素失活促进了Bim介导的糖尿病肾病T细胞的凋亡，并延缓了狼疮的进展。临床上，研究者还发现在SLE患者中，DNT细胞比例升高，其凋亡率降低。此外，与健康组相比，SLE患者表现出Bim水平降低和cullin1代谢水平升高。同时，抑制去甲肾上腺素可诱导SLE患者分离的DNT细胞发生Bim依赖性的凋亡。综上所述，我们的研究结果为狼疮的肾功能提供了直接证据，为狼疮的治疗提供了一种有前景的治疗方法。狼疮治疗中肾脏代谢途径的机制图片来源：https://doi.org/10.1038/s41392-023-01709-9综上所述，研究者发现去甲肾上腺素在维持糖尿病肾病T细胞内稳态和调节系统性红斑狼疮进展方面具有重要作用。MLN4924基因突变抑制或Ube2m基因缺失可通过重建正常的糖尿病肾病T细胞凋亡，显著改善SLE的进展。进一步的实验表明，狼疮小鼠细胞凋亡的阻断确实恢复为去氧尿酸失活，这是由于抑制了Bim泛素化和Bim介导的细胞凋亡的增加所致。临床资料还表明，SLE患者表现为糖尿病肾病T细胞积聚，并存在细胞凋亡缺陷，而药物抑制通过上调Bim蛋白水平促进了糖尿病肾病T细胞的凋亡。这些发现加深了我们对SLE发病机制的理解，并提示神经通路可能是SLE治疗的一个有前途的靶点。参考文献：Yun Zhang et al. Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis. Signal Transduct Target Ther. 2024 Jan 15;9(1):18. doi: 10.1038/s41392-023-01709-9.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！