更新于：2024-05-01

USP22

ubiquitin specific peptidase 22

更新于：2024-05-01

基本信息

别名

Deubiquitinating enzyme 22、KIAA1063、Ubiquitin carboxyl-terminal hydrolase 22

+ [5]

简介

Histone deubiquitinating component of the transcription regulatory histone acetylation (HAT) complex SAGA. Catalyzes the deubiquitination of both histones H2A and H2B, thereby acting as a coactivator. Recruited to specific gene promoters by activators such as MYC, where it is required for transcription. Required for nuclear receptor-mediated transactivation and cell cycle progression.

关联

100 项与 USP22 相关的临床结果

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100 项与 USP22 相关的转化医学

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0 项与 USP22 相关的专利（医药）

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262

项与 USP22 相关的文献（医药）

2024-02-15·Environmental toxicology

Unveiling hormone-stimulated gene mechanisms in prostate cancer: A prognostic model, immune infiltration analysis, and drug sensitivity study.

Article

作者: Zhongru Fan ; Qianqian Yu ; Junpeng Deng ; Ke Wang ; Hongqi Yu ; Xin Fan ; Jianjun Xie

Hormones promote the progression of prostate cancer (PRCA) through the activation of a complex regulatory network. Inhibition of hormones or modulation of specific network nodes alone is insufficient to suppress the entire oncogenic network. Therefore, it is imperative to elucidate the mechanisms underlying the occurrence and development of PRCA in order to identify reliable diagnostic markers and therapeutic targets. To this end, we used publicly available data to analyze the potential mechanisms of hormone-stimulated genes in PRCA, construct a prognostic model, and assess immune infiltration and drug sensitivity. The single-cell RNA-sequencing data of PRCA were subjected to dimensionality reduction clustering and annotation, and the cells were categorized into two groups based on hormone stimulus-related scores. The differentially expressed genes between the two groups were screened and incorporated into the least absolute shrinkage and selection operator machine learning algorithm, and a prognostic model comprising six genes (ZNF862, YIF1A, USP22, TAF7, SRSF3, and SPARC) was constructed. The robustness of the model was validation through multiple methods. Immune infiltration scores in the two risk groups were calculated using three different algorithms. In addition, the relationship between the model genes and immune cell infiltration, and that between risk score and immune cell infiltration were analyzed. Drug sensitivity analysis was performed for the model genes and risk score using public databases to identify potential candidate drugs. Our findings provide novel insights into the mechanisms of hormone-stimulated genes in PRCA progression, prognosis, and drug screening.

2024-02-14·International journal of radiation oncology, biology, physics

USP11 exacerbates radiation induced pneumonitis by activating endothelial cell inflammatory response via OTUD5-STING signaling.

Article

作者: Yiting Tang ; Tingya Wang ; Liming Gu ; Ying Xu ; Zhao Yang ; Wei Zhu ; Qi Zhang ; Judong Luo ; Jianping Cao ; Yang Jiao

PURPOSE:

Radiation induced pneumonitis (RIP) seriously limits the application of radiotherapy in the treatment of thoracic tumors, and its etiology and pathogenesis remain elusive. This study aims to elucidate the role of Ubiquitin-specific peptidase 11 (USP11) in the progression of RIP and the associated underlying mechanisms.

METHODS AND MATERIALS:

The changes of cytokines and infiltrated immune cells were detected by ELISA and IHC after exposed to 20 Gy X-ray with whole thorax irradiation. USP11 expression on endothelial cell proliferation and apoptosis were analyzed by co-staining of CD31/Ki67 and CD31/Caspase-3 in vivo and the production of cytokines and ROS were confirmed by RT-PCR and flow cytometry in vitro. Comprehensive proteome and ubiquitinome were employed for USP11 substrate screening post-radiation. Results were verified by Western blot and Co-IP experiments. rAAV-lung vectors expressing OTUD5 were utilized for localized overexpression of OTUD5 in mouse pulmonary, and IHC were conducted to analyze cytokines expression.

RESULTS:

The progression of RIP was significantly alleviated by reduced the expression of proinflammatory cytokines in both USP11 knockout (Usp11^-/-) and the USP11 inhibitor mitoxantrone treated mice. Likewise, absence of USP11 resulted in decreased permeability of pulmonary vessels and neutrophils and macrophages infiltration. The proliferation rates of endothelial cells were prominently increased in the Usp11^-/- lung, while the apoptosis decreased compared to the Usp11^+/+ following irradiation. Conversely, USP11 overexpression increased proinflammatory cytokines and ROS production in endothelial cells post-radiation. Comprehensive proteome and ubiquitinome analyses indicated that USP11 overexpression upregulated several deubiquitinating enzymes, including USP22, USP33 and OTUD5. We clarified that USP11 deubiquitinating OTUD5 and implicate OTUD5-STING signaling pathway in the progression of inflammatory response in endothelial cells.

CONCLUSIONS:

USP11 exacerbated RIP by triggering an inflammatory response in endothelial cell both in vitro and in vivo, and OTUD5-STING pathway was involved in USP11 promotes RIP. This study provided experimental support for the development of precision intervention strategies targeting USP11 to mitigate RIP.

2024-02-12·Cell communication and signaling : CCS

USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration.

Article

作者: Evangelos Prokakis ; Husam Bamahmoud ; Shaishavi Jansari ; Lena Fritsche ; Alexander Dietz ; Angela Boshnakovska ; Peter Rehling ; Steven A Johnsen ; Julia Gallwas ; Florian Wegwitz

BACKGROUND:

Breast cancer (BC) is the most frequent tumor entity in women worldwide with a high chance of therapeutic response in early- and non-metastatic disease stages. Among all BC subtypes, triple-negative BC (TNBC) is the most challenging cancer subtype lacking effective molecular targets due to the particular enrichment of cancer stem cells (CSCs), frequently leading to a chemoresistant phenotype and metastasis. The Ubiquitin Specific Peptidase 22 (USP22) is a deubiquitinase that has been frequently associated with a CSC-promoting function and intimately implicated in resistance to conventional therapies, tumor relapse, metastasis and overall poor survival in a broad range of cancer entities, including BC. To date, though, the role of USP22 in TNBC has been only superficially addressed.

METHODS:

The current study utilized the MMTV-cre, Usp22^fl/fl transgenic mouse model to study the involvement of USP22 in the stem cell-like properties of the growing mammary tissue. Additionally, we combined high-throughput transcriptomic analyses with publicly available patient transcriptomic data and utilized TNBC culture models to decipher the functional role of USP22 in the CSC characteristics of this disease.

RESULTS:

Interestingly, we identified that USP22 promotes CSC properties and drug tolerance by supporting the oxidative phosphorylation program, known to be largely responsible for the poor response to conventional therapies in this particularly aggressive BC subtype.

CONCLUSIONS:

This study suggests a novel tumor-supportive role of USP22 in sustaining cellular respiration to facilitate the drug-tolerant behavior of HER2⁺-BC and TNBC cells. Therefore, we posit USP22 as a promising therapeutic target to optimize standard therapies and combat the aggressiveness of these malignancies. Video Abstract.

项与 USP22 相关的新闻（医药）

2024-03-26

·今日头条

【Adv. Sci.】北京大学研究团队揭示EZH2对PD-L1蛋白稳定性的最新调控作用

本文为转化医学网原创，转载请注明出处作者：Rainbow 导读： PD-L1的调控是关键问题，它在很大程度上决定了基于免疫检查点抑制剂（ICI）治疗的结果。然而，除了转录水平外，PD-L1的蛋白质稳定性与其功能密切相关，并引起了越来越多的关注。 3月22日，北京大学研究团队在期刊《ADVANCED SCIENCE》上发表题为“EZH2 Inhibition Enhances PD-L1 Protein Stability Through USP22-Mediated Deubiquitination in Colorectal Cancer”的研究论文，本研究揭示了EZH2对PD-L1蛋白稳定性的新调控作用，揭示了EZH2-USP22-PD-L1轴对EZH2抑制剂治疗的耐药机制，验证了EZH2抑制剂与免疫治疗的协同抗癌能力。USP22表达可能是EZH2抑制剂抗癌作用的潜在预测指标。这些发现有助于在临床环境中精确选择患者，从而实现个性化的治疗策略。 https://onlinelibrary.wiley.com/doi/10.1002/advs.202308045 研究背景 01 随着对癌症的深入了解，免疫相关特征，包括避免免疫破坏和促肿瘤炎症，越来越被视为癌症的标志。免疫疗法，特别是基于抗PD-1/PD-L1抗体代表的单克隆抗体的免疫检查点抑制剂（ICI），是改变肿瘤治疗格局最有前景的治疗策略。然而，只有20-40%的患者对ICI有反应，而获得长期疾病缓解的患者更少。各种指标，包括PD-L1（包括exo PD-L1）、TMB、高微卫星不稳定性（MSI-H）和错配修复缺陷（dMMR），被认为能够预测将从免疫治疗中受益的人群。通常，PD-L1表达水平被广泛认为是抗PD-1/PD-L1免疫治疗的潜在生物标志物。结直肠癌（CRC）是全球癌症相关死亡的第二大原因，免疫疗法已被用于具有MSI-H或dMMR的结直肠癌。尽管高PD-L1表达的患者可能会从免疫疗法中受益，但受治疗影响的PD-L1动态表达仍不清楚。PD-L1表达可以受到包括转录、转录后和翻译水平在内的因素调控，人们越来越关注PD-L1翻译后调控的重要性。因此，揭示调控PD-L1表达的机制可能进一步促进对免疫疗法敏感人群的确定，或为联合治疗策略提供新的靶点。非突变表观遗传重编程已被确定为癌症的新标志。它还参与PD-L1表达的调控。zeste同源物2（EZH2）的组蛋白甲基转移酶增强子是多梳抑制复合物2（PRC2）的催化亚基，参与促进肿瘤发展、增殖、侵袭、代谢和抗肿瘤免疫。虽然EZH2参与调节PD-L1表达，目前尚不清楚EZH2是否影响PD-L1蛋白水平的修饰。研究发现 02 在这项研究中，EZH2抑制增强了PD-L1的表达和蛋白质的稳定性，去泛素化酶泛素特异性肽酶22（USP22）被确定为这一过程中的关键介质。EZH2抑制转录上调USP22表达，上调USP22进一步稳定PD-L1。EZH2抑制剂与抗PD-1免疫检查点阻断疗法的结合改善了肿瘤微环境，增强了对免疫治疗的敏感性，并发挥了协同抗癌作用。此外，敲低USP22可以潜在地增强EZH2抑制剂对结肠癌的治疗效果。这些发现揭示了EZH2抑制剂通过上调PD-L1在肿瘤免疫逃避中的新作用，这一缺点可以通过联合ICI免疫疗法来弥补。因此，这些发现为EZH2-USP22-PD-L1调控轴提供了宝贵的见解，为结合免疫检查点阻断和基于EZH2抑制剂的表观遗传疗法的优化提供了启示，以实现更高的癌症治疗疗效和准确性。 EZH2通过USP22介导的去泛素化效应增强PD-L1蛋白稳定性研究结论 03 综上所述，本研究揭示了EZH2对PD-L1蛋白稳定性的新调控作用，揭示了EZH2-USP22-PD-L1轴对EZH2抑制剂治疗的耐药机制，验证了EZH2抑制剂与免疫治疗的协同抗癌能力。USP22表达可能是EZH2抑制剂抗癌作用的潜在预测指标。这些发现有助于在临床环境中精确选择患者，从而实现个性化的治疗策略。参考资料： https://onlinelibrary.wiley.com/doi/10.1002/advs.202308045 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 线上｜03月28日 ▶Twist全外显子组测序应用新篇章 🕓 上海｜03月28日-30日 ▶2024（第二届）合成生物学与生物医学健康大会参会指南公布！ 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 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！点击对应文字查看详情

免疫疗法

2022-12-14

·生物谷

南医大王曦等揭示表观遗传修饰可提高对病原体感染的防御能力

在遭遇病原体感染期间，造血系统会从正常模式切换到紧急模式，这提高了对病原体的防御能力。如果身体启动了紧急造血模式，这表明免疫系统处于警报状态，这有两个不同的目的：紧急造血模式能够补充和增加在感染或炎症在遭遇病原体感染期间，造血系统会从正常模式切换到紧急模式，这提高了对病原体的防御能力。如果身体启动了紧急造血模式，这表明免疫系统处于警报状态，这有两个不同的目的：紧急造血模式能够补充和增加在感染或炎症期间消耗的免疫细胞；紧急造血模式能使整个免疫系统进入预激活状态，有助于更快地清除感染。这种紧急造血模式的特点包括血液干细胞分裂增加，成熟白细胞平衡向有利于髓细胞（巨噬细胞和粒细胞）的方向转变。通常，这种紧急模式是由病原体的典型分子成分或促炎信号（例如某些干扰素）触发的。但在这个过程中，血液干细胞和祖细胞中究竟发生了什么？有没有一种启动紧急程序的细胞开关呢？德国癌症研究中心Nikolaus Dietlein、南京医科大学王曦等人在 Science 子刊 Science Immunology 发表了题为：Usp22 is an intracellular regulator of systemic emergency hematopoiesis 的研究论文。该研究表明，去泛素化酶USP22通过对单泛素化修饰的H2B组蛋白（H2Bub1）的去泛素化，作为系统紧急造血的细胞内调节因子，USP22的缺失或抑制，以细胞自主的方式促进紧急造血、增强先天免疫，从而提高对病原体感染的防御能力。这项研究证明了表观遗传修饰提高了对病原体感染的防御能力，也提示了我们使用药物来抑制USP22可能有助于提高个体对病原体的免疫防御能力。组蛋白H2B的单泛素化是一种由RNF20/RNF40 E3泛素连接酶复合物催化的活化组蛋白修饰，单泛素化修饰的H2B组蛋白（H2Bub1）主要存在于高表达基因的转录区。在细胞中，当病毒感染或干扰素刺激时，干扰素刺激基因（ISG）位点上的H2Bub1水平升高，这对预防感染很重要。而H2Bub1可以被去泛素化酶USP22重新去泛素化。这表明USP22可能参与限制了体内干扰素刺激基因（ISG）的表达及其下游生物学结果，包括启动紧急造血模式。那么，H2Bub1和USP22是触发血液干细胞紧急程序的开关吗？研究团队购机那里一个Usp22基因条件性敲除小鼠模型，该小鼠模型的造血干细胞不表达去泛素化酶USP22。结果显示，这些小鼠具有所有关键特征的紧急造血模式运行时没有任何可检测到的感染或干扰素水平的增加。这些小鼠比正常小鼠更能抵御单核增生李斯特菌的感染。此外，它们血液中重要的清道夫细胞——中性粒细胞，能够更能成功地吞噬感染的细菌。正如预期那样，这些造血干细胞USP22基因关闭的小鼠模型的血细胞中的遗传物质也有明显更多的表观遗传H2Bub1修饰。H2Bub1水平的升高似乎是使免疫系统处于待命状态的警报按钮，让免疫系统在最初接触病原体后进入高度防御警戒状态。而在USP22去除H2Bub1修饰后，在正常小鼠中会终止这种警报。 H2Bub1和USP22也存在于人类细胞中，根据目前的研究，它们在人类细胞和在小鼠细胞中的功能相当。总的来说，这项研究发现，在无感染或炎症的情况下，造血细胞中Usp22基因缺失的小鼠显示出显著的全身性紧急造血模式。在功能上，Usp22基因的缺失导致嗜中性粒细胞吞噬能力增强，并增强了对单核增生李斯特菌感染的先天保护。在分子水平上，这种紧急造血模式与髓系启动的转录特征、增强的线粒体呼吸以及先天和适应性免疫和炎症有关，许多炎症基因的增强表达与位点特异性H2Bub1水平升高有关。 Usp22缺失增强了抗菌先天性免疫这些结果表明，存在着一种可调的表观遗传状态，以细胞自主的方式促进系统紧急造血，以增强先天保护，识别潜在的免疫增强途径。这项研究在小鼠中证明了表观遗传修饰提高了对病原体感染的防御能力，但USP22的缺失会如何影响人类造血干细胞和祖细胞仍是未知的，还需要进一步研究。但这项研究提示了我们，使用药物来抑制USP22可能有助于提高个体对病原体的免疫防御能力。

并购

2022-12-09

·Science Daily

Epigenetic emergency switch improves defense against infections

During infections, the hematopoietic system switches from normal to emergency mode. This improves the defense against the pathogens. Scientists have now found an epigenetic switch in blood stem cells and progenitor cells of mice that can trigger the switch from one mode to the other. During infections, the hematopoietic system switches from normal to emergency mode. This improves the defense against the pathogens. Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now found an epigenetic switch in blood stem cells and progenitor cells of mice that can trigger the switch from one mode to the other. If the emergency program of hematopoiesis starts up in the body, this signals an alarm state of the immune system and serves two different purposes: Compared to hematopoiesis in "normal mode," the emergency program results in increased replenishment of immune cells that are consumed during infections or inflammations. In addition, the emergency program puts the entire immune system into a pre-activation that helps clear infections more quickly. Characteristic of the emergency program are, for example, an increased division rate of blood stem cells and a shift in the balance of mature white blood cells in favor of myeloid cells (macrophages and granulocytes). Normally, the emergency program is triggered by typical molecular components of pathogens or by pro-inflammatory messenger substances such as certain interferons. But what happens in the blood stem cells and progenitor cells? Is there a cellular switch that triggers the emergency program? Scientists led by Nikolaus Dietlein and Hans-Reimer Rodewald of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) targeted a specific epigenetic modification, abbreviated H2Bub1. It is involved in switching on genes that are activated by interferon as a result of a viral infection and that are important for the defense against infection. The modification, which attaches to the packaging proteins of the DNA, the histones, is removed again by the enzyme USP22. Could H2Bub1 and USP22 be the sought-after switch that triggers the emergency program in the blood stem cell? The researchers led by Rodewald investigated this in mice in whose blood stem cells USP22 was genetically switched off. In these animals, the emergency program of hematopoiesis with all its key features ran without any detectable infection or increased interferon levels. The genetically modified animals were better able to fight off infection with the bacterium Listeria monocytogenes than normal mice. In addition, important scavenger cells in their blood, neutrophil granulocytes, were more successful at engulfing bacteria. As expected, the genetic material in the blood cells of the gene-modified animals also had significantly more of the epigenetic H2Bub1 modifications. "The increased H2Bub1 level seems to be the alarm button that puts the immune system on standby. In particular, this puts the innate immune defense, which is especially important during initial contact with a pathogen, into heightened defense alert," says Nikolaus Dietlein, first author of the current publication. USP22, which removes the H2Bub1 modification, terminates the alert in normal animals. H2Bub1 and USP22 are also found in human cells and, according to current research, perform comparable functions there to those in mice. Hans-Reimer Rodewald says: "In mice, we were able to show that an epigenetic modification improves the defense against infection. However, how the loss of USP22 affects human hematopoietic stem and progenitor cells is still unknown and should now be investigated. Inhibition of USP22 by drugs could possibly one day help to improve the immune defense against pathogens. So far, however, this is currently still unproven and needs to be tested in further studies."