更新于：2024-09-19

TRIM5

更新于：2024-09-19

基本信息

别名

RING finger protein 88、RING-type E3 ubiquitin transferase TRIM5、RNF88

+ [4]

简介

Capsid-specific restriction factor that prevents infection from non-host-adapted retroviruses. Blocks viral replication early in the life cycle, after viral entry but before reverse transcription. In addition to acting as a capsid-specific restriction factor, also acts as a pattern recognition receptor that activates innate immune signaling in response to the retroviral capsid lattice. Binding to the viral capsid triggers its E3 ubiquitin ligase activity, and in concert with the heterodimeric ubiquitin conjugating enzyme complex UBE2V1-UBE2N (also known as UBC13-UEV1A complex) generates 'Lys-63'-linked polyubiquitin chains, which in turn are catalysts in the autophosphorylation of the MAP3K7/TAK1 complex (includes TAK1, TAB2, and TAB3). Activation of the MAP3K7/TAK1 complex by autophosphorylation results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes, thereby leading to an innate immune response in the infected cell. Restricts infection by N-tropic murine leukemia virus (N-MLV), equine infectious anemia virus (EIAV), simian immunodeficiency virus of macaques (SIVmac), feline immunodeficiency virus (FIV), and bovine immunodeficiency virus (BIV) (PubMed:17156811). Plays a role in regulating autophagy through activation of autophagy regulator BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2 (PubMed:25127057). Also plays a role in autophagy by acting as a selective autophagy receptor which recognizes and targets HIV-1 capsid protein p24 for autophagic destruction (PubMed:25127057).

关联

靶点

CCR5 x TRIM5

作用机制

CCR5拮抗剂 [+1]

在研机构-

原研机构

Great Ormond Street Hospital for Children NHS Foundation Trust

在研适应症-

非在研适应症

X连锁联合免疫缺陷疾病

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 TRIM5 相关的临床试验

NCT05207657 / Recruiting临床1/2期

Phase I/II, Non-randomised, Single-centre, Open-label Study of pCHIM-p47 (Lentiviral Vector Transduced CD34+ Cells) in Patients With p47 Autosomal Recessive Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) is a rare inherited disorder in which patients suffer from severe infection and inflammation. The first indications of disease usually appear in early childhood. The basic defect has been found to be lie in specialised white blood cells called phagocytic cells, which are responsible for engulfing and destroying germs. In CGD, there is a defect in an enzyme (known as the NADPH-oxidase) that is responsible for generating bleach like substances that are important for killing some important germs. In one form of the disease known as p47 AR-CGD (which accounts for 30% of patients), there are defined mistakes in a gene called NCF1. This gene is needed to form a key component of NADPH-oxidase.
In many cases, patients can be protected from infection by constant intake of antibiotics. However, in others potentially life-threatening infections break through. In some cases patients also develop serious inflammation requiring high doses of drugs such as steroids. CGD can be cured by bone marrow transplant and the best results are available when a matched sibling donor is available. Transplant from unmatched donors have a much worse outcome and as a result alternative treatments for patients without a matched donor are highly desirable.
Gene therapy of p47 AR-CGD is performed by introducing a normal copy of the human NCF-1 gene into the blood forming stem cells in the patients' bone marrow by using a gene carrier (in this study called a lentiviral vector). After treatment of the bone marrow cells in a specialised laboratory they are given back to the patient and will grow into functional phagocytic cells. There have been no previous clinical trials for patients with p47 AR-CGD however there have been previous gene therapy clinical trials conducted in the UK for patients with the most common form of CGD, known as X-CGD.

开始日期2023-03-20

申办/合作机构

Great Ormond Street Hospital for Children NHS Foundation Trust

NCT03601286 / Recruiting临床1期

Phase I/II Study of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan

Severe combined immunodeficiency disorder (SCID) is a heterogeneous group of inherited disorders characterized by a profound reduction or absence of T lymphocyte function, resulting in lack of both cellular and humoral immunity. SCID arises from a variety of molecular defects which affect lymphocyte development and function. The most common form of SCID is an X-linked form (SCID-X1), which accounts for 30-50% of all cases. SCID-X1 is caused by defects in the common cytokine receptor gamma chain, which was originally identified as a component of the high affinity interleukin-2 receptor (IL2RG).
Allogeneic haematopoietic stem cell transplantation (HSCT), which replaces the patient's bone marrow with that of a healthy donor, is the only treatment that definitively restores the normal function of the bone marrow. HSCT is the first choice of treatment for patients with signs of bone marrow failure and a fully-matched related donor. However, patients without a fully-matched related donor have much worse overall outcomes from HSCT.
This study will investigate whether patients with SCID-X1 without a fully matched related donor may benefit from gene therapy. To do this the investigators propose to perform a phase I/II clinical trial to evaluate the safety and efficacy (effect) of gene therapy for SCID-X1 patients using a lentivirus delivery system containing the IL2RG gene. Up to 5 eligible SCID-X1 patients will undergo mobilisation and harvest of their haematopoietic stem precursor cells (HPSCs). In the laboratory the disabled lentivirus will be used to insert a normal human IL2RG gene into the patient's harvested HPSCs. Patients will receive chemotherapy conditioning prior to cell infusion, in order to enhance grafting. The genetically corrected stem cells will then be re-infused into the patient. Patients will be followed up for 2 years. This trial will determine whether gene therapy for SCID-X1 using a lentiviral vector is safe, feasible and effective

开始日期2018-12-21

申办/合作机构

Great Ormond Street Hospital for Children NHS Foundation Trust

100 项与 TRIM5 相关的临床结果

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100 项与 TRIM5 相关的转化医学

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0 项与 TRIM5 相关的专利（医药）

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303

项与 TRIM5 相关的文献（医药）

2024-08-01·Experimental Cell Research

N6-methyladenosine modification of linc-OIP5 confers paclitaxel resistance in breast cancer through a DDX5-dependent mechanism

Article

作者: Jian, Qiwei ; Wang, Xuedong ; Wang, Xinping ; Zhang, Ziyun ; Li, Ping ; Wang, Yueping

Chemoresistance is a significant obstacle in the treatment of breast cancer (BC). Due to its diverse composition, the causes of chemoresistance in BC are complex and have not been completely understood. In this article, we explored the mechanism of N6-methyladenosine (m6A)-modified long intervening noncoding RNA (linc)-OIP5 in BC chemoresistance. We successfully constructed drug-resistant cell lines MCF-7/P and MDA-MB-231/P by exposing parental MDA-MB-231 and MCF-7 cells to escalating doses of paclitaxel (PTX) and revealed multiple m6A methylation modification sites on linc-OIP5 according to the predictive analysis of the SRAMP database. Linc-OIP5 expression and m6A modification were up-regulated in PTX-resistant BC cells. Inhibition of m6A modification or linc-OIP5 knockdown facilitated PTX-resistant and parental BC cell apoptosis and repressed proliferation and migration. Mechanistically, linc-OIP5 bound to TRIM5 and reduced the ubiquitination of DDX5, thus stabilizing the DDX5 protein. Additionally, DDX5 overexpression partly abrogated the suppressing effects of inhibited m6A modification or si-linc-OIP5 on cell proliferation, migration and PTX resistance. These findings indicate that m6A-modified linc-OIP5 reduced DDX5 ubiquitination and enhanced DDX5 stability by binding to TRIM5, thereby promoting BC cell proliferation, migration and PTX resistance, and inhibiting apoptosis.

2024-06-01·Virus Research

Can inflammatory plasma proteins predict Long COVID or Fatigue severity after SARS-CoV-2 infection?

Article

作者: Freuer, Dennis ; Warm, Tobias Dominik ; Kirchberger, Inge ; Hyhlik-Dürr, Alexander ; Goßlau, Yvonne ; Schmitz, Timo ; Meisinger, Christa ; Linseisen, Jakob

OBJECTIVETo investigate whether specific immune response plasma proteins can predict an elevated risk of developing Long COVID symptoms or fatigue severity after SARS-CoV-2 infection.METHODSThis study was based on 257 outpatients with test-confirmed SARS-CoV-2 infection between February 2020 and January 2021. At least 12 weeks after the acute infection, 92 plasma proteins were measured using the Olink Target 96 immune response panel (median time between acute infection and venous blood sampling was 38.8 [IQR: 24.0-48.0] weeks). The presence of Long COVID symptoms and fatigue severity was assessed 115.8 [92.5-118.6] weeks after the acute infection by a follow-up postal survey. Long COVID (yes/no) was defined as having one or more of the following symptoms: fatigue, shortness of breath, concentration or memory problems. The severity of fatigue was assessed using the Fatigue Assessment Scale (FAS). In multivariable-adjusted logistic and linear regression models the associations between each plasma protein (exposure) and Long COVID (yes/no) or severity of fatigue were investigated.RESULTSNine plasma proteins were significantly associated with Long COVID before, but not after adjusting for multiple testing (FDR-adjustment): DFFA, TRIM5, TRIM21, HEXIM1, SRPK2, PRDX5, PIK3AP1, IFNLR1 and HCLS1. Moreover, a total of 10 proteins were significantly associated with severity of fatigue before FDR-adjustment: SRPK2, ITGA6, CLEC4G, HEXIM1, PPP1R9B, PLXNA4, PRDX5, DAPP1, STC1 and HCLS1. Only SRPK2 and ITGA6 remained significantly associated after FDR-adjustment.CONCLUSIONSThis study demonstrates that certain immune response plasma proteins might play an important role in the pathophysiology of Long COVID and severity of fatigue after SARS-CoV-2 infection.

2024-05-01·Cell Reports

Mapping of susceptibility loci for Ebola virus pathogenesis in mice

Article

作者: Miller, Darla R ; Feldmann, Heinz ; Vernon, Michael J ; Midkiff, Bentley R ; Catanzaro, Nicholas J ; Bell, Timothy A ; Martinez, David R ; Hubbard, Miranda L ; Hock, Pablo ; Shaw, Ginger D ; Gully, Kendra L ; Baric, Ralph S ; Nguyen, Cameron ; Wilkerson, Gregory K ; Leist, Sarah R ; Graham, Rachel L ; Cowley, Dale O ; Marzi, Andrea ; Thomas, Tina ; De la Cruz, Gabriela E ; Montgomery, Stephanie A ; Haddock, Elaine ; de Villena, Fernando Pardo Manuel ; Meade-White, Kimberly ; Ferris, Martin T ; Feldmann, Friederike ; Schughart, Klaus ; Schäfer, Alexandra ; Furuyama, Wakako

Ebola virus (EBOV), a major global health concern, causes severe, often fatal EBOV disease (EVD) in humans. Host genetic variation plays a critical role, yet the identity of host susceptibility loci in mammals remains unknown. Using genetic reference populations, we generate an F2 mapping cohort to identify host susceptibility loci that regulate EVD. While disease-resistant mice display minimal pathogenesis, susceptible mice display severe liver pathology consistent with EVD-like disease and transcriptional signatures associated with inflammatory and liver metabolic processes. A significant quantitative trait locus (QTL) for virus RNA load in blood is identified in chromosome (chr)8, and a severe clinical disease and mortality QTL is mapped to chr7, which includes the Trim5 locus. Using knockout mice, we validate the Trim5 locus as one potential driver of liver failure and mortality after infection. The identification of susceptibility loci provides insight into molecular genetic mechanisms regulating EVD progression and severity, potentially informing therapeutics and vaccination strategies.

项与 TRIM5 相关的新闻（医药）

2023-08-10

·生物谷

Nature：老药新用抗猴痘，作用更持久，且不易导致耐药性

该研究揭示了细胞蛋白TRIM5α能够抑制包括猴痘病毒（MPXV）在内的多种正痘病毒，而亲环蛋白A （CypA）和病毒蛋白C6则会拮抗TRIM5α。更重要的是，该研究进一步证实了现有的靶向亲环蛋白A 近日，中国疾控中心发布的数据显示，2023年7月份，中国内地（不含港澳台）新增报告491例猴痘确诊病例，这491人均为男性。此前世界卫生组织（WHO）发布的数据显示，几乎全部（98%以上）猴痘确诊病例为男同性恋者。猴痘（monkeypox），是一种人畜共患病，1958年首次在用于研究的猴子中发现，主要在动物中传播。1970年首次在刚果（金）发现人类猴痘病例，此后猴痘一直在非洲的一些国家流行，包括尼日利亚、刚果（金）和中非共和国等。非洲以外地区的猴痘病例通常是因为去非洲旅游所感染。而在2022年上半年，猴痘开始在欧洲和北美地区传播，2022年7月23日，世界卫生组织（WHO）总干事谭德赛宣布，猴痘疫情为“国际关注的突发公共卫生事件”（PHEIC）。天花作为一种疾病，早在1979年就已经被根除，但导致天花的天花病毒，仍然被保存在两个高度安全的实验室里——一个在美国，一个在俄罗斯。天花病毒被用于生物恐怖袭击的威胁导致了一种名为特考韦瑞（Tecovirimat）的药物被批准用于治疗天花，这是一种广谱包膜蛋白抑制剂，对正痘类病毒表现出良好的抗病毒活性。在过去一年里，特考韦瑞被用于治疗严重的猴痘患者，但这也导致了猴痘病毒多种耐药株的出现。因此，急需开发新的猴痘治疗药物。 2023年8月9日，剑桥大学和牛津大学的 Geoffrey Smith 教授团队（赵奕祺博士、陆泳旭博士为共同第一作者）在国际顶尖学术期刊 Nature 上发表了题为：TRIM5α restricts poxviruses and is antagonized by CypA and the viral protein C6 的研究论文。该研究揭示了细胞蛋白TRIM5α能够抑制包括猴痘病毒（MPXV）在内的多种正痘病毒，而亲环蛋白A （CypA）和病毒蛋白C6则会拮抗TRIM5α。更重要的是，该研究进一步证实了现有的靶向亲环蛋白A （CypA）的药物能够有效抑制包括猴痘病毒和天花病毒在内的多种正痘病毒的感染和复制，此外，由于这些药物不直接作用于病毒，这意味着病毒也将更难以进化出耐药性。论文共同通讯作者、剑桥大学 Geoffrey Smith 教授表示，该研究确定的药物比目前用来治疗猴痘的药物作用更持久，预计它也会对一系列其他痘病毒有效，包括天花病毒。痘苗病毒（VACV）是用于根除天花的活疫苗，目前正被用于对猴痘高危人群（男同性恋者）进行免疫接种。痘苗病毒（VACV）、牛痘病毒（CPXV）、猴痘病毒（MPXV）、骆驼痘病毒（CMLV）和天花病毒（VARV）都是正痘病毒，具有免疫交叉保护作用。在根除天花之后，人们还在继续研究痘苗病毒（VACV），将其作为疫苗开发平台。一旦痘病毒感染宿主细胞，这些病毒必须保护自己免受宿主细胞蛋白的攻击，这些细胞蛋白会限制病毒的复制和传播。这项研究开始于一个简单的观察发现——痘苗病毒（VACV）感染会导致人类细胞中TRIM5α水平降低。为了找出背后的原因，研究团队使用CRISPR-Cas9基因编辑技术构建了敲除TRIM5的人类细胞，然后分别过表达TRIM5α、TRIM5γ或TRIM5δ，证实了TRIM5α具有抗病毒活性，TRIM5α通过其SPRY结构域与正痘病毒衣壳蛋白L3结合，减少病毒复制并激活先天免疫。该研究还发现，包括痘苗病毒、兔痘病毒、牛痘病毒、猴痘病毒、骆驼痘病毒和天花病毒在内的几种正痘病毒对TRIM5α的攻击产生了两种防御措施——首先，病毒产生了C6蛋白通过RING结构域与TRIM5结合，诱导其蛋白酶体依赖性降解；其次，亲环蛋白A （CypA）通过与病毒衣壳蛋白L3相互作用被招募到病毒工厂和病毒颗粒中，以拮抗TRIM5α。现在已经有许多以亲环蛋白A（CypA）为靶点的药物，例如CsA，以及CsA的非免疫抑制衍生物Alisporivir和NIM811，实验结果显示，这些药物能够良好的抑制包括猴痘病毒在内的一系列正痘病毒的感染和复制。 CsA是一种已被FDA批准上市免疫抑制剂，用于器官移植、自身免疫疾病的治疗，还具有抗HIV作用，但其存在比较严重的肝肾毒性等副作用。而Alisporivir和NIM811是两款无免疫抑制活性的CsA衍生物，目前至少已进行了2期临床试验。由于这些药物是作用于人体的亲环蛋白A（CypA），而非作用于病毒本身，因此很难导致病毒耐药性的出现。这些结果为使用CsA衍生物对抗正痘病毒（包括猴痘病毒和天花病毒）的试验提供了依据。 Geoffrey Smith 教授表示，这项研究结果完全出乎意料，一开始进行这项研究是为了了解痘病毒是如何逃避宿主防御的，完全没想到这可能会发现治疗猴痘病毒和其它正痘病毒的药物。