更新于：2024-09-19

RFFL

更新于：2024-09-19

基本信息

别名

CARP-2、CARP2、Caspase regulator CARP2

+ [13]

简介

E3 ubiquitin-protein ligase that regulates several biological processes through the ubiquitin-mediated proteasomal degradation of various target proteins. Mediates 'Lys-48'-linked polyubiquitination of PRR5L and its subsequent proteasomal degradation thereby indirectly regulating cell migration through the mTORC2 complex. Ubiquitinates the caspases CASP8 and CASP10, promoting their proteasomal degradation, to negatively regulate cell death downstream of death domain receptors in the extrinsic pathway of apoptosis. Negatively regulates the tumor necrosis factor-mediated signaling pathway through targeting of RIPK1 to ubiquitin-mediated proteasomal degradation. Negatively regulates p53/TP53 through its direct ubiquitination and targeting to proteasomal degradation. Indirectly, may also negatively regulate p53/TP53 through ubiquitination and degradation of SFN. May also play a role in endocytic recycling.

关联

100 项与 RFFL 相关的临床结果

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100 项与 RFFL 相关的转化医学

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0 项与 RFFL 相关的专利（医药）

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项与 RFFL 相关的文献（医药）

2024-11-01·Biochemical and Biophysical Research Communications

Enhanced CFTR modulator efficacy in ΔF508 CFTR mouse organoids by ablation of RFFL ubiquitin ligase

Article

作者: Okiyoneda, Tsukasa ; Kamada, Yuka ; Hinata, Daichi ; Fukuda, Ryosuke ; Ishiguro, Hiroshi

The most common CFTR mutant in cystic fibrosis (CF), ΔF508 CFTR, is eliminated by ubiquitination even in the presence of CF drugs, reducing their therapeutic efficacy. RFFL is one of the ubiquitin ligases that remove ΔF508 CFTR from the cell surface despite treatment with the triple combination of CFTR modulators (TEZ/ELX/IVA) used clinically. Although RFFL knockdown has been shown to enhance the efficacy of TEZ/ELX/IVA in cell culture models, its impact in mouse models has not been evaluated. Here, we demonstrate that RFFL ablation significantly improves the effect of TEZ/ELX/IVA, resulting in enhanced function of ΔF508 CFTR in mouse organoids. Since RFFL knockout mice showed no significant abnormalities, our findings support RFFL inhibition as a promising strategy to improve CFtreatment.

2024-03-01·Computers in Biology and Medicine

A novel PCDscore based on programmed cell death-related genes can effectively predict prognosis and therapy responses of colon adenocarcinoma

Article

作者: Li, Yanke ; Li, Hao ; Jing, Jingjing ; Sun, Liping ; Peng, Yangjie ; Ma, Rui ; Wu, Yijun ; Ouyang, Cheng

Emerging evidence suggests a correlation between oncogenesis and programmed cell death (PCD). However, comprehensive studies that incorporate all identified PCD-related genes to guide colon adenocarcinoma (COAD) prognosis and precision treatment strategies are lacking. In this study, a series of bioinformatics analyses were comprehensively conducted using data from the TCGA-COAD, GSE17538, and GSE39582 cohorts. A total of 21 PCD-associated prognostic genes were identified through univariate Cox analysis. LASSO and multivariate Cox methods were employed to establish a prognostic gene signature (ALOX12, HSPA1A, IL13, MID2, RFFL, and SLC39A8) and the corresponding scoring system, termed PCDscore, which exhibited robust predictive ability. The ssGSEA and ESTIMATE algorithms were utilized to evaluate the tumor microenvironment of COAD. The high PCDscore group demonstrated a poorer prognosis, characterized by lower CD4⁺ T cell infiltration and a higher stromal score. In contrast, the low PCDscore group exhibited sensitivity to common chemotherapy drugs such as Cisplatin and 5-Fluorouracil. Single-cell sequencing analysis further revealed that the high-PCDscore group displayed a lower proportion of CD4⁺ T cells. Colorectal cancer samples from the years 2013-2017 were employed to validate the PCDscore, while those from 2018 to 2019 served as a temporal external validation set for the PCDscore. In vitro experimental results indicated that the overexpression of SLC39A8 inhibited the proliferation and invasion of colorectal cancer cells. The study developed a novel PCDscore system based on the analysis of genes related to all identified PCD types, providing valuable insights into clinical prognosis and drug sensitivity for patients with COAD.

2024-03-01·Journal of Biological Chemistry

E3 ubiquitin ligase rififylin has yin and yang effects on rabbit cardiac transient outward potassium currents (Ito) and corresponding channel proteins

Article

作者: Bronk, Peter ; Roder, Karim ; Turan, Nilüfer N ; Lu, Yichun ; Dhakal, Saroj ; Zhong, Mingwang ; Zeltzer, Zachary A ; Karma, Alain ; Koren, Gideon ; Najman-Licht, Yonatan B ; Kabakov, Anatoli Y

Genome-wide association studies have reported a correlation between a SNP of the RING finger E3 ubiquitin protein ligase rififylin (RFFL) and QT interval variability in humans (Newton-Cheh et al., 2009). Previously, we have shown that RFFL downregulates expression and function of the human-like ether-a-go-go-related gene potassium channel and corresponding rapidly activating delayed rectifier potassium current (I_Kr) in adult rabbit ventricular cardiomyocytes. Here, we report that RFFL also affects the transient outward current (I_to), but in a peculiar way. RFFL overexpression in adult rabbit ventricular cardiomyocytes significantly decreases the contribution of its fast component (I_to,f) from 35% to 21% and increases the contribution of its slow component (I_to,s) from 65% to 79%. Since I_to,f in rabbits is mainly conducted by Kv4.3, we investigated the effect of RFFL on Kv4.3 expressed in HEK293A cells. We found that RFFL overexpression reduced Kv4.3 expression and corresponding I_to,f in a RING domain-dependent manner in the presence or absence of its accessory subunit Kv channel-interacting protein 2. On the other hand, RFFL overexpression in Kv1.4-expressing HEK cells leads to an increase in both Kv1.4 expression level and I_to,s, similarly in a RING domain-dependent manner. Our physiologically detailed rabbit ventricular myocyte computational model shows that these yin and yang effects of RFFL overexpression on I_to,f, and I_to,s affect phase 1 of the action potential waveform and slightly decrease its duration in addition to suppressing I_Kr. Thus, RFFL modifies cardiac repolarization reserve via ubiquitination of multiple proteins that differently affect various potassium channels and cardiac action potential duration.

项与 RFFL 相关的新闻（医药）

2023-08-10

·生物制品圈

重要成果！山大齐鲁医院首次揭示乳腺癌治疗可靠新靶点

导读：转录因子ETS-1激活的LINC01016可明显促进细胞增殖活性，增强细胞迁移能力，阻滞S期细胞周期，降低细胞凋亡率。近日，山大齐鲁医院研究团队在《Cell Death＆Disease》上发表题为“ETS-1-activated LINC01016 over-expression promotes tumor progression via suppression of RFFL-mediated DHX9 ubiquitination degradation in breast cancers”的研究报告。通过RNA pull-down分析和质谱分析，报告确定LINC01016通过阻止E3泛素连接酶RFFL与DHX9结合，从而抑制DHX9蛋白酶体降解，从而竞争性结合并稳定DHX9蛋白。这最终导致细胞内DHX9表达增加，并激活PI3K/AKT信号，p-AKT、Bcl-2和MMP-9参与。本研究首次揭示了LINC01016/DHX9/PI3K/AKT轴在BC进展中发挥关键作用，因此，LINC01016可能成为BC患者的潜在治疗靶点。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-023-06016-3研究背景 01 乳腺癌(BC)是最常见的恶性肿瘤之一，2020年有230万新诊断病例和68.5万以上妇女死亡。三阴性乳腺癌(TNBC)占所有乳腺癌的15%，与其他亚型相比，TNBC的预后较差。许多研究已经在遗传学和表观遗传学水平上探索了TNBC的致病基础。然而，调控肿瘤发生发展的详细分子机制尚不清楚，亟待进一步研究。蛋白质编码基因约占人类基因组的2%，其中大部分细胞内转录物为非编码RNA，如长链非编码RNA(long non-coding RNA, lncRNA)，其长度为>200个核苷酸，参与多种生物学过程。lncRNA的异常表达在肿瘤的发生、发展或转移中起着重要作用。尽管有这些发现，单个lncRNA在BC中的具体作用仍然不清楚。研究团队已经鉴定出胃癌(GC)样本中差异表达的lncRNA，并提交至基因表达综合(GEO)数据库(GSE72307)。LINC01016在有淋巴结转移的胃癌组织中表达高于无淋巴结转移的胃癌组织。LINC01016定位于染色体6q21.31，在多种肿瘤类型中检测到其表达上调。Yun等人鉴定出LINC01016是在甲状腺癌中上调并与肿瘤发展相关的几个lncRNA之一。Philip等发现LINC01016在雌激素受体(ER)阳性亚型乳腺癌中表达上调，可能与预后不良相关。然而，其功能和潜在的调控机制尚未被探索。LINC01016是否在TNBC中起作用尚未见报道。LINC01016在包括TNBC亚型在内的BC组织中表达上调，并与淋巴结转移相关。研究结果强调了LINC01016在人类乳腺癌中的潜在致癌作用。研究团队确定LINC01016通过竞争性抑制E3泛素连接酶RFFL与DHX9蛋白结合并稳定DHX9蛋白促进TNBC细胞增殖和侵袭，从而激活DHX9介导的PI3K/AKT信号通路加速乳腺肿瘤进展。研究成果 02 EdU实验和MTS实验显示ETS-1显著增强BC细胞的增殖。同样，ETS-1在Transwell实验和伤口愈合中增强了BC细胞的迁移和侵袭。ETS-1过表达降低了BC细胞的凋亡率，促进细胞周期向S期进展。这些结果表明，ETS-1激活了LINC01016的转录，促进了BC进展。ETS-1促进BC细胞恶性进展从功能的角度，研究人员发现LINC01016上调细胞内DHX9蛋白水平，而不影响DHX9 mRNA的表达。研究人员假设LINC01016是DHX9的翻译后调节因子。DHX9存在多种不同的翻译后修饰，可影响蛋白质的功能和稳定性，而泛素化修饰是目前研究较多的DHX9蛋白调控方法。许多不同的DHX9残基可以被泛素化，包括赖氨酸1048、146、191、417、857和1037 (https://www.genecards.org/)。在本研究中，研究人员发现LINC01016在BC细胞中过表达与DHX9泛素化降低相关，而当LINC01016被敲低时，观察到相反的结果。通过Co-IP和MS分析，研究人员进一步确定了E3泛素连接酶RFFL负责DHX9的泛素化。先前的研究表明，RFFL可诱导一系列靶蛋白的泛素化和随后的蛋白酶体降解。在本研究中，研究人员发现RFFL过表达足以通过泛素化和随后的蛋白酶体依赖性降解机制降低DHX9蛋白水平。研究人员推测LINC01016通过DHX9和RFFL介导的泛素化依赖机制促进BC细胞的恶性。LINC01016与DHX9物理结合，显著削弱了DHX9与RFFL的共沉淀，并将DHX9与RFFL隔离，从而阻止了DHX9的泛素化和随后的降解。通过mRNA测序，研究人员发现DHX9可能通过激活PI3K/AKT信号通路发挥其恶性生物学行为。Western blotting分析显示，过表达LINC01016可增加DHX9、MMP-9、p-AKT和Bcl-2的表达。LINC01016促进AKT磷酸化的具体机制将在未来探索。综上所述，研究人员发现ETS -1诱导的LINC01016上调增强了BC细胞的增殖，迁移，凋亡抗性和细胞周期进程。诱导后，LINC01016通过竞争性结合抑制RFFL介导的DHX9泛素化，从而保护这一解旋酶不被蛋白酶体降解，并最终增强PI3K/AKT信号传导。因此，LINC01016和LINC01016介导的DHX9/PI3K/AKT信号通路可能成为TNBC患者治疗的可行靶点。参考资料：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-023-06016-3