更新于：2024-09-19

IFIT5

更新于：2024-09-19

基本信息

别名

IFIT-5、IFIT5、interferon induced protein with tetratricopeptide repeats 5

+ [6]

简介

Interferon-induced RNA-binding protein involved in the human innate immune response. Has a broad and adaptable RNA structure recognition important for RNA recognition specificity in antiviral defense. Binds precursor and processed tRNAs as well as poly-U-tailed tRNA fragments (PubMed:25092312, PubMed:23317505, PubMed:23774268). Specifically binds single-stranded RNA bearing a 5'-triphosphate group (PPP-RNA), thereby acting as a sensor of viral single-stranded RNAs. Single-stranded PPP-RNAs, which lack 2'-O-methylation of the 5' cap and bear a 5'-triphosphate group instead, are specific from viruses, providing a molecular signature to distinguish between self and non-self mRNAs by the host during viral infection. Directly binds PPP-RNA in a non-sequence-specific manner (PubMed:23334420). Also recognizes and selectively binds AT-rich dsDNA (PubMed:23774268). Additionally, as a mediator in innate immunity, regulates positively IKK-NFKB signaling by sinergizing the recruitment of IKK to MAP3K7 (PubMed:26334375).

关联

100 项与 IFIT5 相关的临床结果

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100 项与 IFIT5 相关的转化医学

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0 项与 IFIT5 相关的专利（医药）

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118

项与 IFIT5 相关的文献（医药）

2024-08-01·Poultry Science

Goose IFIT5 positively regulates goose astrovirus replication in GEF cells

Article

作者: Zhang, Xiaozhan ; Li, Ruixue ; Yang, Xia ; Wang, Zeng ; Zhai, Saimin ; Gao, Shenyan ; Zhao, Jun

Interferon-induced protein with tetratricopeptide repeats (IFITs), a family of proteins strongly induced by type I interferon (IFN-I), are deeply involved in many cellular and viral processes. IFIT5, the sole protein in this family found in birds, also plays a crucial role in regulating virus infection. In this study, goose IFIT5 (gIFIT5) was first cloned from peripheral blood lymphocyte (PBL) and phylogenetic analysis showed that it was highly homologous with duck IFIT5 (dIFIT5), sharing 94.6% identity in amino acid sequence. Subsequently, the expression kinetics of gIFIT5 during goose astrovirus (GAstV) infection and the regulatory effect of gIFIT5 on GAstV proliferation were evaluated. Results showed that the mRNA and protein expression level of gIFIT5 was greatly induced by GAstV infection, especially at 12 hpi. Importantly, gIFIT5 could conversely promote GAstV replication in GEF cells. Virus titers in gIFIT5 overexpression group were significantly higher than those in control group at 12 and 24 hpi. Western blot and quantitative real-time PCR (qRT-PCR) further demonstrated that the production of viral cap protein was significantly facilitated in gIFIT5-transfected group. Collectively, GAstV facilitates self-replication via promoting gIFIT5 expression.

2024-05-30·Blood

Epigenetic control over the cell-intrinsic immune response antagonizes self-renewal in acute myeloid leukemia

Article

作者: Alla, Vijay ; Lenz, Georg ; Hennig, Thorben ; Wolf, Sebastian ; Huber, Otmar ; Oellerich, Thomas ; Dugas, Martin ; Hartmann, Wolfgang ; Walter, Carolin ; Jayavelu, Ashok Kumar ; Schliemann, Christoph ; Arteaga, Maria Francisca ; Mikesch, Jan-Henrik ; Müller-Tidow, Carsten ; Seifert, Franca ; Serve, Hubert ; Angenendt, Linus ; Frenz, Joris Maximillian ; Felipe Fumero, Eloísa ; Mann, Matthias

AbstractEpigenetic modulation of the cell-intrinsic immune response holds promise as a therapeutic approach for leukemia. However, current strategies designed for transcriptional activation of endogenous transposons and subsequent interferon type-I (IFN-I) response, show limited clinical efficacy. Histone lysine methylation is an epigenetic signature in IFN-I response associated with suppression of IFN-I and IFN-stimulated genes, suggesting histone demethylation as key mechanism of reactivation. In this study, we unveil the histone demethylase PHF8 as a direct initiator and regulator of cell-intrinsic immune response in acute myeloid leukemia (AML). Site-specific phosphorylation of PHF8 orchestrates epigenetic changes that upregulate cytosolic RNA sensors, particularly the TRIM25-RIG-I-IFIT5 axis, thereby triggering the cellular IFN-I response-differentiation-apoptosis network. This signaling cascade largely counteracts differentiation block and growth of human AML cells across various disease subtypes in vitro and in vivo. Through proteome analysis of over 200 primary AML bone marrow samples, we identify a distinct PHF8/IFN-I signature in half of the patient population, without significant associations with known clinically or genetically defined AML subgroups. This profile was absent in healthy CD34+ hematopoietic progenitor cells, suggesting therapeutic applicability in a large fraction of patients with AML. Pharmacological support of PHF8 phosphorylation significantly impairs the growth in samples from patients with primary AML. These findings provide novel opportunities for harnessing the cell-intrinsic immune response in the development of immunotherapeutic strategies against AML.

2024-03-01·Vascular Pharmacology

COVID-19 plasma induces subcellular remodelling within the pulmonary microvascular endothelium

Article

作者: Bennett, Matthew ; Dewerchin, Mieke ; Beqqali, Abdelaziz ; Veizades, Stefan ; Caporali, Andrea ; Wereski, Ryan ; Brittan, Mairi ; Mills, Nicholas L ; Berkeley, Bronwyn ; Rodor, Julie ; Cholewa-Waclaw, Justyna ; Baker, Andrew H ; Li, Ziwen ; Passi, Rainha

BACKGROUNDCOVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect multiple organ systems, including the pulmonary vasculature. Endothelial cells (ECs) are thought to play a key role in the propagation of COVID-19, however, our understanding of the exact scale of dysregulation sustained by the pulmonary microvasculature (pMV) remains incomplete. Here we aim to identify transcriptional, phenotypic, and functional changes within the pMV induced by COVID-19.METHODS AND RESULTSHuman pulmonary microvascular endothelial cells (HPMVEC) treated with plasma acquired from patients hospitalised with severe COVID-19 were compared to HPMVEC treated with plasma from patients hospitalised without COVID-19 but with other severe illnesses. Exposure to COVID-19 plasma caused a significant functional decline in HPMVECs as seen by a decrease in both cell viability via the WST-1 cell-proliferation assay and cell-to-cell barrier function as measured by electric cell-substrate impedance sensing. High-content imaging using a Cell Painting image-based assay further quantified morphological variations within sub-cellular organelles to show phenotypic changes in the whole endothelial cell, nucleus, mitochondria, plasma membrane and nucleolus morphology. RNA-sequencing of HPMVECs treated with COVID-19 plasma suggests the observed phenotype may, in part, be regulated by genes such as SMAD7, BCOR, SFMBT1, IFIT5 and ZNF566 which are involved in transcriptional regulation, protein monoubiquitination and TGF-β signalling.CONCLUSION AND IMPACTDuring COVID-19, the pMV undergoes significant remodelling, which is evident based on the functional, phenotypic, and transcriptional changes seen following exposure to COVID-19 plasma. The observed morphological variation may be responsible for downstream complications, such as a decline in overall cellular function and cell-to-cell barrier integrity. Moreover, genes identified through bulk RNA sequencing may contribute to our understanding of the observed phenotype and assist in developing strategies that can inform the rescue of the dysregulated endothelium.

项与 IFIT5 相关的新闻（医药）

2023-04-07

·CPHI制药在线

研发 | 干扰素抗病毒作用机制及其在疾病治疗中的应用

关注并星标CPHI制药在线干扰素（interferon IFN）是一类重要的细胞因子，能直接参与上皮细胞的抗病毒免疫反应，介导天然免疫应答诱导 IFN 刺激基因（interferon stimulated gene，ISG）的表达，从而使机体快速建立针对病毒侵染的天然免疫防线。根据干扰素结构特点，结合受体和生物活性，人干扰素可分为3类，即Ⅰ、Ⅱ和Ⅲ型干扰素，其基因分别位于人9p21-22、12q24.1和19q13.13 染色体。在人类三种类型的干扰素中，Ⅰ型干扰素主要包括 IFN-α，IFN-β等20种亚型，Ⅱ型干扰素只有 IFN-γ，Ⅲ型干扰素包括 IL-29 ( IFN-λ1) 等 4 种亚型。大多数被病毒感染的细胞都可以产生Ⅰ型干扰素，分泌的 IFN-α/β 可与邻近未被感染的细胞上的共同受体结合并启动旁分泌信号级联反应。Ⅰ型和Ⅲ型干扰素被认为是经典的抗病毒干扰素，α 型干扰素是临床治疗抗病毒的主要亚型，主要分为α-1b、α-2b、α-2a 等亚型。近期研究表明，Ⅲ型干扰素与黏膜免疫有重要的关系，而IFN-γ 也具有良好的病毒抑制特性。干扰素抗病毒作用机制干扰素激活分子在病毒复制周期的许多阶段表现出抗病毒活性，包括病毒进入、转录、RNA 稳定性、翻译、成熟和释放等阶段。这种作用是在抗病毒基因表达的调节下进行的。 ①病毒的附着和进入。HPSE 是一种编码乙酰肝素酶的干扰素诱导基因（ISG），HPSE 的异位表达可广泛抑制甲病毒、黄病毒、副粘病毒和诺如病毒。病毒进入是多个ISG 靶向的阶段，IFITM 蛋白质是经典的 ISG，可破坏多种包膜病毒的进入，IFITM 蛋白将病毒颗粒运输到降解溶酶体中，可有效地阻止病毒的进入。CH25H 是一种干扰素诱导酶，可将胆固醇转化为25-羟基胆固醇(25-HC)，25-HC 膜扰动功能抑制病毒进入。最近发现的靶向病毒进入的 ISG人类核受体辅激活因子 7 ( NCOA7) 可以结合液泡H + -ATP 酶，促进囊泡酸化和内吞物的降解，从而抑制通过内吞作用进入细胞的多种病毒的感染。此外，在病毒基因表达开始之前的进入后病毒过程也可以被 ISG 干扰，以及某些ISG 还能特异性地阻断病毒通过核孔复合体。 ②病毒基因组的扩增。IFI16是一种 IFN 诱导的 DNA 传感器，被证明可以干扰人类巨细胞病毒基因的转录。RBBP6 是一种泛素E3 连接酶，RBBP6可直接与埃博拉病毒 VP30 蛋白相互作用，从而阻止VP30与病毒NP 蛋白的相互作用并干扰病毒转录。干扰素能强烈诱导2-5A 寡合成酶/核糖核酸酶L系统，核糖核酸酶L被双链 RNA 激活可降解所有单链 RNA，从而抑制病毒复制。 ③病毒蛋白质的翻译。在病毒复制周期中，干扰素通过多种机制靶向病毒蛋白翻译。干扰素通过PKR 基因启动子中的 ISRE 和 GAS 刺激蛋白激酶 R( protein kinase R，PKR) 的表达，进而将翻译起始因子 eIF2-α 的51位Ser 磷酸化。eIF2-α-GTP 是启动病毒翻译所必需的。eIF-2B从每轮翻译起始后回收 eIF2-α-GDP，进行鸟嘌呤核苷酸交换，产生eIF2-α-GTP。然而，eIF-2B优先与 eIF2-α 的磷酸化形式结合。因此，eIF-2B 的细胞储备被隔离在非活性复合物 eIF2α-GDP-eIF-2B中，从而快速抑制病毒蛋白的翻译。此外，PKR 还通过调节 STAT1 的丝氨酸磷酸化和 IκB 的磷酸化，从而激活NF-κB 依赖性基因，在细胞增殖、肿瘤抑制和信号转导中发挥作用。IFIT 家族(包括人类的 IFIT1、IFIT2、IFIT3和IFIT5) 利用多种机制靶向病毒蛋白的产生，如结合 eiF3C 或 eiF3E 以抑制翻译起始。 ④病毒颗粒的组装和释放。病毒复制周期的后期包括病毒粒子组装、运输和从细胞中释放。与病毒复制周期的早期阶段相比，针对这些步骤的 ISG较少。Tetherin 是一种跨膜蛋白，可以将萌芽病毒粒子锚定到细胞表面并阻止它们释放。CNP( 2-环核苷酸-3-磷酸二酯酶) 结合Gag 并抑制 HIV-1颗粒组装。鸟苷酸结合蛋白 5( GBP5) 阻碍病毒包膜糖蛋白组装病毒粒子。另外，Ⅰ型干扰素作为抗病毒细胞因子发挥作用。IFN-α 激活 NK 细胞，进而破坏病毒和其他靶细胞，增加 B 细胞的增殖，B 细胞分泌抗病原体的抗体，通过上调表面细胞MHCⅠ类分子的表达，增强CD8+T 细胞的反应。Ⅰ型干扰素还上调 IL-12Rb，增加 MHC Ⅱ类分子的表达。IFNα-1b 可以增加单核细胞 MHCⅡ抗原的表达。炎症性干扰素信号促进和调节巨噬细胞和树突状细胞的发育、成熟和刺激能力。这些效应促进抗病毒抗体的产生，限制病毒复制以限制系统性病毒持续性。干扰素在疾病治疗中的应用自从干扰素产品在我国上市以来，获批的治疗适应症已扩大到几十种疾病，主要包括治疗病毒性疾病和肿瘤。干扰素在治疗皮肤科疾病方面也已得到广泛应用，包括带状疱疹、生殖器疱疹，尖锐湿疣、寻常疣、扁平疣和皮肤肿瘤等。此外，干扰素在抗炎症反应以及维持机体生理动态平衡方面也发挥着重要作用。 ①皮肤科疾病。2021年《中国尖锐湿疣临床诊疗指南》强烈推荐皮损内注射干扰素，证据等级为A ，2020 年欧洲皮肤病与性病学会发布了《生殖器传染性软疣管理指南》，将干扰素作为免疫抑制剂，2019 年《带状疱疹临床路径》中推荐干扰素作为免疫增强剂，2018 年德国颁布的《HPV 感染及其相关病变的诊疗指南》中将 IFN-α(局部用或病灶内用药)作为首选治疗方案之一。2014 年发布的《英国肛门-生殖器疱疹指南》提及有证据显示三氟胸苷单独或联合 IFN-α 可以治疗耐受性生殖器疱疹。并且，根据现有临床试验来看，IFN-α 也在实际临床应用中显示出了很好的效果。 ②抗病毒药物和免疫调节。作为广谱抗病毒药物和免疫调节剂，干扰素在临床上早已广泛用于治疗各种儿童病毒性疾病，《重组人干扰素α1b 在儿科应用的专家共识》，《手足口病诊疗指南》和《α干扰素在儿科临床合理应用专家共识》等众多指南共识明确阐明干扰素可用于小儿病毒性肺炎、手足口病、疱疹性咽峡炎和毛细支气管炎等。 ③肝病治疗。α-干扰素是治疗慢性活动性乙型肝炎的首选药物，2019 年《中国慢性乙型肝炎防治指南》推荐 PEG-IFN-α 和 IFN-α用于治疗慢性乙型肝炎。干扰素也是治疗丙型肝炎的有效药物之一，可抑制急性丙型肝炎转化为慢性丙型肝炎。 ④治疗SARS-CoV-2。干扰素吸入给药能够以更小的剂量实现高气道暴露，快速达到肺部起效浓度，减少全身副作用。我国国家卫生健康委员会发布的多版《新型冠状病毒肺炎诊疗方案》中均提出可用 IFN-α 雾化吸入进行抗病毒治疗，在新冠肺炎诊疗方案试行第八版中阐明抗病毒治疗可单独用 IFN-α，成人每次500万U或相当剂量，加入灭菌注射用水 2mL，2次/d，雾化吸入，疗程不超过 10 d。此外，IFN-α 还可与利巴韦林联合应用。此外，干扰素能够通过抗细胞增殖，免疫调节和抑制肿瘤血管形成等方式对肿瘤生长起到抑制作用，临床主要用来治疗白血病、淋巴瘤、Kaposi肉瘤，黑色素瘤、肾癌、多发性骨髓瘤等。干扰素也可用于治疗多发性硬化症等自身免疫性疾病。干扰素是我国第一个投放市场的基因工程药物，自1986年美国FDA及1989 年我国SFDA 批准投放市场以来，干扰素的治疗适应症逐年扩大，目前国际上批准的治疗适应证已有数十种，取得了重要的社会效益和良好的经济效益。作为机体免疫调节和抗病毒物质，干扰素一直受到人们的关注，干扰素的基础和临床研究已取得了较大进展。根据国家药品监督管理局网站公示，我国目前批准干扰素相关产品有92个，型别包括 α-1b、α-2a、α-2b和 γ，以及长效干扰素 PEG-IFN-α2b。剂型包括注射液、滴眼液、阴道泡腾片、乳膏、软膏、凝胶、喷雾剂和栓剂。PEG-IFN-α2a、PEG-IFN-α2b、IFNα-1b、IFNα-2a 和 IFNα-2b 等已进入了 2020 版国家医保目录，这一举措显著降低了老百姓的看病成本，切实保障了人民健康。参考资料 [1]郑丽舒,段招军,罗迪贤,陈宏翔,邓启文,侯云德.干扰素的发展历史、现状与展望[J].皮肤科学通报,2021,38(06):479-484+1. [2]庞立丽,段招军,罗迪贤,陈宏翔,邓启文,侯云德.干扰素作用机制的研究进展[J].皮肤科学通报,2021,38(06):485-491+2. [3]金丽,苏强,周建华,马忠仁.Ⅰ型和Ⅲ型干扰素抗病毒作用机制的研究进展[J].中国生物制品学杂志,2021,34(04):481-486. 智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~