FBXO38

更新于：2025-05-07

基本信息

别名

F-box only protein 38、F-box protein 38、Fbx38

+ [4]

简介

Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of PDCD1/PD-1, thereby regulating T-cells-mediated immunity (PubMed:30487606). Required for anti-tumor activity of T-cells by promoting the degradation of PDCD1/PD-1; the PDCD1-mediated inhibitory pathway being exploited by tumors to attenuate anti-tumor immunity and facilitate tumor survival (PubMed:30487606). May indirectly stimulate the activity of transcription factor KLF7, a regulator of neuronal differentiation, without promoting KLF7 ubiquitination (By similarity).

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100 项与 FBXO38 相关的临床结果

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100 项与 FBXO38 相关的转化医学

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0 项与 FBXO38 相关的专利（医药）

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项与 FBXO38 相关的文献（医药）

2024-10-01·Cancer Immunology Research

The E3 Ubiquitin Ligase FBXO38 Maintains the Antitumor Function of Natural Killer Cells by Sustaining IL15R Signaling

Article

作者: Tian, Zhigang ; Wang, Xianwei ; Xu, Chenqi ; Sun, Haoyu ; Sun, Rui ; Zheng, Xiaodong ; Shi, Yongjing ; Peng, Hui

AbstractNatural killer (NK) cells are the main innate antitumor effector cells but their function is often constrained in the tumor microenvironment. It has been reported that the E3 ligase FBXO38 accelerates PD-1 degradation in tumor-infiltrating T cells to unleash their cytotoxic function. In this study, we found that the transcriptional levels of FBXO38 in intratumoral NK cells of patients with cancer and tumor-bearing mice were significantly lower than in peritumoral NK cells. Conditional knockout of FBXO38 in NK cells accelerated tumor growth and increased tumor metastasis. FBXO38 deficiency resulted in impaired proliferation and survival of tumor-infiltrating NK (TINK) cells. Mechanistically, FBXO38 deficiency enhanced TGF-β signaling, including elevating expression of Smad2 and Smad3, which suppressed expression of the transcription factor Eomes and further reduced expression of surface IL15Rβ and IL15Rγc on NK cells. Consequently, FBXO38 deficiency led to TINK cell hyporesponsiveness to IL15. Consistent with these observations, FBXO38 mRNA expression was positively correlated with the proliferation of TINK cells in multiple human tumors. To study the therapeutic potential of FBXO38, mice bearing human tumors were treated with FBXO38 overexpressed human primary NK cells and showed a significant reduction in tumor size and prolonged survival. In conclusion, our results suggest that FBXO38 sustains NK-cell expansion and survival to promote antitumor immunity and have potential therapeutic implications as they suggest FBXO38 could be harnessed to enhance NK cell–based cancer immunotherapy.

2024-10-01·Advanced Science

PTBP3 Mediates IL‐18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer

Article

作者: Zhu, Yi‐di ; Shu, Yi‐jun ; Yang, Zi‐yi ; Liu, Shi‐lei ; Zhang, Yu‐han ; Dong, Ping ; Wang, Hua‐kai ; Wu, Xiang‐song ; Yang, Yue ; Gong, Wei ; Tang, Qiu‐yi ; Zhao, Cheng ; Zhao, Jing‐wei

AbstractGallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA‐seq analysis, it is found high expression of the splicing factor polypyrimidine region‐ binding protein 3 (PTBP3) in GBC. Multi‐omics analysis revealed that PTBP3 promoted exon skipping of interleukin‐18 (IL‐18), resulting in the expression of ΔIL‐18, an isoform specifically expressed in tumors. That ΔIL‐18 promotes GBC immune escape by down‐regulating FBXO38 transcription levels in CD8+T cells to reduce PD‐1 ubiquitin‐mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL‐18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL‐18 production displayed anti‐tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL‐18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL‐18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL‐18 pre‐mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.

2024-08-15·Cancer Research

Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes

Article

作者: Giles, Graham G. ; Zheng, Wei ; Chen, Zhishan ; Gruber, Stephen B. ; Peters, Ulrike ; Shu, Xiao-Ou ; Pearlman, Rachel ; Casey, Graham ; Yang, Yaohua ; Zhang, Yunjing ; Cai, Qiuyin ; Wen, Wanqing ; Jia, Guochong ; Lin, Weiqiang ; Zhang, Qingrun ; Rennert, Gad ; Long, Jirong ; Tao, Ran ; Guo, Xingyi ; Phipps, Amanda ; He, Jingni ; Vodicka, Pavel ; Su, Xinwan ; Ping, Jie

AbstractAlternative polyadenylation (APA) modulates mRNA processing in the 3′-untranslated regions (3′ UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. In this study, we conducted large APA-wide association studies to investigate associations between APA levels and cancer risk. Genetic models were built to predict APA levels in multiple tissues using genotype and RNA sequencing data from 1,337 samples from the Genotype-Tissue Expression project. Associations of genetically predicted APA levels with cancer risk were assessed by applying the prediction models to data from large genome-wide association studies of six common cancers among European ancestry populations: breast, ovarian, prostate, colorectal, lung, and pancreatic cancers. A total of 58 risk genes (corresponding to 76 APA sites) were associated with at least one type of cancer, including 25 genes previously not linked to cancer susceptibility. Of the identified risk APAs, 97.4% and 26.3% were supported by 3′-UTR APA quantitative trait loci and colocalization analyses, respectively. Luciferase reporter assays for four selected putative regulatory 3′-UTR variants demonstrated that the risk alleles of 3′-UTR variants, rs324015 (STAT6), rs2280503 (DIP2B), rs1128450 (FBXO38), and rs145220637 (LDHA), significantly increased the posttranscriptional activities of their target genes compared with reference alleles. Furthermore, knockdown of the target genes confirmed their ability to promote proliferation and migration. Overall, this study provides insights into the role of APA in the genetic susceptibility to common cancers.Significance: Systematic evaluation of associations of alternative polyadenylation with cancer risk reveals 58 putative susceptibility genes, highlighting the contribution of genetically regulated alternative polyadenylation of 3′UTRs to genetic susceptibility to cancer.

项与 FBXO38 相关的新闻（医药）

2024-08-13

·今日头条

“免疫逃逸”新机制！上海交大发文：揭示癌症免疫治疗新靶点

【导读】胆囊癌(GBC)是胆道系统最常见的恶性肿瘤，目前的治疗效果较差。异常的选择性剪接与多种肿瘤的发生有关。 8月8日，上海交通大学研究团队在期刊《Advanced Science》上发表了研究论文，题为“PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer”，本研究中，研究人员结合GEO数据库和GBC mRNA-seq分析，发现剪接因子聚嘧啶区域结合蛋白3 (PTBP3)在GBC中高表达。多组学分析显示，PTBP3促进了白细胞介素-18 (IL-18)的外显子跳跃，导致ΔIL-18的表达，这是一种肿瘤特异性表达的亚型。ΔIL-18通过下调CD8+T细胞中FBXO38的转录水平来减少PD-1泛素介导的降解，从而促进GBC免疫逃逸。通过HuPBMC小鼠模型，研究人员证实了PTBP3和ΔIL-18在促进GBC生长中的作用，并表明阻断ΔIL-18产生的反义寡核苷酸显示出抗肿瘤活性。此外，H3K36me3通过MRG15募集PTBP3促进IL-18外显子跳跃，从而耦合IL-18转录和选择性剪接过程。特别是，研究还发现H3K36甲基转移酶SETD2与hnRNPL结合，从而干扰PTBP3与IL-18前体mRNA的结合。总的来说，本研究为异常的选择性剪接机制如何影响免疫逃逸提供了新的见解，并为改善GBC免疫治疗提供了潜在的新视角。 https://onlinelibrary.wiley.com/doi/10.1002/advs.202406633 背景知识 01 胆囊癌虽然是胆道系统的高度恶性肿瘤，但由于缺乏典型的临床症状和早期诊断工具，往往诊断较晚。目前胆囊癌手术切除是公认的治疗方法，但能够进行手术治疗的患者很少，各种辅助治疗方式的疗效有限。因此，有必要更深入地阐明胆囊癌的发病机制，寻找有效的治疗靶点。在高等真核生物中，遗传信息从DNA到成熟mRNA的传递通常需要前体mRNA的剪接。大多数含有内含子的基因经历简单的内含子剪接和外显子连接，这一过程被称为组成性剪接。选择性剪接提供了额外的基因调控模式，可以显著增加转录本数量，增强蛋白质的结构和功能多样性。虽然许多蛋白质的不同剪接亚型在正常条件下是有益的，但在病理条件下的选择性剪接可能会导致有害影响。例如，在肿瘤组织中，广泛的选择性剪接异常已被证明有助于肿瘤进展。选择性剪接主要有5种方式，其中外显子跳跃是最常见的。选择性剪接相关rna结合蛋白(RBPs)在肿瘤发生过程中调节选择性剪接事件中发挥重要作用。例如，DDX17可调节选择性剪接产生促肝癌转移的PXN-AS1致癌亚型。此外，之前的研究表明，一个不含POU结构域的八聚体结合蛋白通过增强DLG1的致癌RNA剪接促进胆囊癌细胞增殖。然而，研究人员对胆囊癌中选择性剪接异常的认识还远远不够。 PTBP3通过ΔIL-18促进胆囊癌免疫逃逸 02 基于12例胆囊癌患者的mRNA-seq数据，研究人员采用Spearman分析探讨PTBP3与免疫细胞浸润的关系。如图1A所示，NK细胞和CD8+T细胞与PTBP3表达呈显著负相关。CD8+T细胞是参与肿瘤发生、发展的重要免疫细胞，在肿瘤细胞免疫逃逸中发挥重要作用。PTBP3的表达与CD8+T细胞浸润呈负相关，而IL-18 PSI值与CD8+T细胞浸润呈正相关。基于这些结果，研究人员使用了肿瘤细胞和CD8+T细胞共培养系统，表明在肿瘤细胞中PTBP3敲低增强了CD8+T细胞的抗肿瘤作用。ELISA检测结果显示，与敲低PTBP3的NOZ和ZJU-0430细胞共培养后，CD8+T细胞产生更多的颗粒酶B和IFNγ。免疫检查点的失调在许多恶性肿瘤的免疫逃避中起着重要作用。其中，PD-1 /PD-L1轴的破坏被证明与肿瘤进展显著相关。mRNA-seq分析结果显示，在12例配对的胆囊癌标本中，PTBP3与PD-L1的表达无显著相关性，但与PD-1的表达呈正相关。蛋白质免疫印迹实验结果显示，在CD8+T细胞共培养体系中，敲低胆囊癌细胞PTBP3对PD-L1的表达无明显影响，但显著降低了CD8+T细胞中PD-1的表达。接下来，研究人员构建了HuPBMC小鼠模型，在体内研究PTBP3在胆囊CD8+T细胞抗肿瘤功能和免疫治疗敏感性中的作用。通过流式细胞术对HuPBMC小鼠模型进行验证，证实小鼠体内人CD45+细胞的百分比大于60%。体内实验表明，通过皮下肿瘤体积和质量测量，PTBP3敲低显著抑制HuPBMC肿瘤生长，并提高胆囊癌免疫治疗的敏感性。此外，研究人员对皮下肿瘤进行了mIHC，发现在PTBP3敲低组中浸润的CD8+T细胞比对照组更多。相反，在NOG小鼠皮下肿瘤模型中，PTBP3敲低后对肿瘤生长没有显著影响，表明PTBP3敲低介导的抗肿瘤效应是CD8+T细胞依赖的。图1：PTBP3通过ΔIL-18促进胆囊癌免疫逃逸为了研究PTBP3是否通过ΔIL-18介导胆囊癌免疫逃逸，研究人员在肿瘤细胞中过表达PTBP3，并用ASO4处理肿瘤细胞以减少ΔIL-18的产生。流式细胞术分析显示，ASO4部分逆转了PTBP3过表达引起的细胞凋亡抑制。ELISA检测结果也表明ASO处理能够挽救PTBP3过表达导致的CD8+ T细胞颗粒酶B和IFNγ分泌的减少。此外，蛋白质免疫印迹实验显示ASO4处理降低了CD8+T细胞中PD-1的表达，也降低了PTBP3诱导的PD-1表达的增加。使用HuPBMC小鼠模型进行的体内实验也证实，ASO4可减少PTBP3过表达引起的肿瘤进展，并显示出显著的抗肿瘤作用。mIHC结果显示，ASO4治疗增加了CD8+T细胞在肿瘤内的浸润，与CD8+T细胞的抗肿瘤作用相一致。在药物安全性方面，ASO4处理的小鼠主要脏器(心、肝、肾、肺)未见明显病理改变。综上所述，ptbp3介导的促肿瘤作用是CD8+T细胞依赖的，ASO4可能在胆囊癌的治疗中具有潜在价值。研究小结 03 综上所述，研究人员发现剪接因子PTBP3在胆囊癌中表达显著上调，并与胆囊癌患者的预后相关。PTBP3对胆囊癌细胞的生物学行为无明显影响，但通过促进IL-18外显子跳跃促进肿瘤细胞的免疫逃逸。在机制上，通过外显子跳跃产生的ΔIL-18通过降低FBXO38转录水平，减少了CD8+T细胞中PD-1泛素介导的降解。在选择性剪接调控过程中，H3K36me3通过MRG15招募PTBP3促进外显子跳跃，并偶联IL-18转录和选择性剪接。同时，hnRNPL通过SHI结构域与SETD2结合，通过抑制PTBP3与IL-18前体mRNA的结合来损害IL-18外显子跳跃。本研究加深了对胆囊癌进展过程中异常选择性剪接事件的认识，并为胆囊癌的免疫治疗提供了新的治疗靶点。【参考资料】 https://onlinelibrary.wiley.com/doi/10.1002/advs.202406633 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 线上｜08月15日 19:00-20:30 ▶ “脑类器官前沿：揭秘遗传机制，重塑神经退行性疾病研究未来”线上研讨会欢迎您的参与！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会欢迎您的参与！点击对应文字查看详情

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