更新于：2024-05-01

OTUD1

OTU deubiquitinase 1

更新于：2024-05-01

基本信息

别名

DUBA-7、DUBA7、OTDC1

+ [3]

简介

Deubiquitinating enzyme that specifically hydrolyzes 'Lys-63'-linked polyubiquitin to monoubiquitin (PubMed:23827681). Required for the stability and translation of a subset mRNAs with a high abundance of rare codons by mediating deubiquitination of 40S ribosomal protein RPS10/eS10, thereby antagonizing ZNF598-mediated 40S ubiquitination (PubMed:36445135). The abundance of rare codons in mRNAs can limit the translation rate and can lead to ribosome collisions that trigger activation of ribosome quality control (RQC) pathway by ZNF598 (PubMed:36445135). OTUD1-mediated deubiquitination prevents activation of the RQC and subsequent dissociation of ribosomes and stimulates formation of polysomes and translation (PubMed:36445135).

关联

100 项与 OTUD1 相关的临床结果

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100 项与 OTUD1 相关的转化医学

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0 项与 OTUD1 相关的专利（医药）

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110

项与 OTUD1 相关的文献（医药）

2024-02-21·Oncogene

The BAP1 nuclear deubiquitinase is involved in the nonhomologous end-joining pathway of double-strand DNA repair through interaction with DNA-PK.

Article

作者: Hiroki Sato ; Tatsuo Ito ; Takuo Hayashi ; Shigehisa Kitano ; Hediye Erdjument-Bromage ; Matthew J Bott ; Shinichi Toyooka ; Marjorie Zauderer ; Marc Ladanyi

BRCA1-associated protein 1 (BAP1) has emerged as a major tumor suppressor gene in diverse cancer types, notably in malignant pleural mesothelioma (DPM), and has also been identified as a germline cancer predisposition gene for DPM and other select cancers. However, its role in the response to DNA damage has remained unclear. Here, we show that BAP1 inactivation is associated with increased DNA damage both in Met-5A human mesothelial cells and human DPM cell lines. Through proteomic analyses, we identified PRKDC as an interaction partner of BAP1 protein complexes in DPM cells and 293 T human embryonic kidney cells. PRKDC encodes the catalytic subunit of DNA protein kinase (DNA-PKcs) which functions in the nonhomologous end-joining (NHEJ) pathway of DNA repair. Double-stranded DNA damage resulted in prominent nuclear expression of BAP1 in DPM cells and phosphorylation of BAP1 at serine 395. A plasmid-based NHEJ assay confirmed a significant effect of BAP1 knockdown on cellular NHEJ activity. Combination treatment with X-ray irradiation and gemcitabine (as a radiosensitizer) strongly suppressed the growth of BAP1-deficient cells. Our results suggest reciprocal positive interactions between BAP1 and DNA-PKcs, based on phosphorylation of BAP1 by the latter and deubiquitination of DNA-PKcs by BAP1. Thus, functional interaction of BAP1 with DNA-PKcs supports a role for BAP1 in NHEJ DNA repair and may provide the basis for new therapeutic strategies and new insights into its role as a tumor suppressor.

2024-02-13·Nature communications

Aggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer.

Article

作者: Yurou Chen ; Yulong Qiang ; Jiachen Fan ; Qian Zheng ; Leilei Yan ; Guanlan Fan ; Xiaofei Song ; Nan Zhang ; Qiongying Lv ; Jiaqiang Xiong ; Jingtao Wang ; Jing Cao ; Yanyan Liu ; Jie Xiong ; Wei Zhang ; Feng Li

Aggresomes are the product of misfolded protein aggregation, and the presence of aggresomes has been correlated with poor prognosis in cancer patients. However, the exact role of aggresomes in tumorigenesis and cancer progression remains largely unknown. Herein, the multiomics screening reveal that OTUD1 protein plays an important role in retaining ovarian cancer stem cell (OCSC) properties. Mechanistically, the elevated OTUD1 protein levels lead to the formation of OTUD1-based cytoplasmic aggresomes, which is mediated by a short peptide located in the intrinsically disordered OTUD1 N-terminal region. Furthermore, OTUD1-based aggresomes recruit ASK1 via protein-protein interactions, which in turn stabilize ASK1 in a deubiquitinase-independent manner and activate the downstream JNK signaling pathway for OCSC maintenance. Notably, the disruption of OTUD1-based aggresomes or treatment with ASK1/JNK inhibitors, including ibrutinib, an FDA-approved drug that was recently identified as an MKK7 inhibitor, effectively reduced OCSC stemness (OSCS) of OTUD1^high ovarian cancer cells. In summary, our work suggests that aggresome formation in tumor cells could function as a signaling hub and that aggresome-based therapy has translational potential for patients with OTUD1^high ovarian cancer.

2024-01-22·International journal of radiation oncology, biology, physics

OTUB1 targets CHK1 for deubiquitinating and stabilizing to facilitate lung cancer progression and radioresistance.

Article

作者: Juanjuan Wang ; Yuting Liu ; Di Wu ; Chen Tian ; Jiaqi Gao ; Qifan Yang ; Xiaohua Hong ; Fei Fei Gu ; Kai Zhang ; Yue Hu ; Shuangbing Xu ; Li Liu ; Yulan Zeng

PURPOSE:

Radioresistance of lung cancer poses a significant challenge when it comes to the treatment of advanced, recurrent, and metastatic cases. OTUB1, known as Ovarian tumor domain ubiquitin aldehyde binding 1, is a key member of the deubiquitinase OTU superfamily. This protein is involved in various cellular functions, including cell proliferation, iron death, lipid metabolism and cytokine secretion, as well as immune response processes. However, its specific role and molecular mechanism in lung cancer radioresistance remain to be clarified.

METHODS AND MATERIALS:

The expression levels of OTUB1 in paired lung cancer tissues were determined by immunohistochemistry (IHC). In vitro and in vivo experiments were conducted to investigate the impact of OTUB1 on the growth and proliferation of lung cancer. Coimmunoprecipitation and Western blotting techniques were performed to examine the interaction between OTUB1 and CHK1. The DNA damage response was measured by comet tailing and immunofluorescence staining. KEGG pathways and GO terms were analyzed based on RNA-seq.

RESULTS:

Our findings reveal a high frequency of OTUB1 overexpression, which is associated with an unfavorable prognosis in patients diagnosed with lung cancer. Through comprehensive investigations, we demonstrate that OTUB1 depletion impairs the process of DNA damage repair and overcomes radioresistance. In terms of the underlying mechanism, our study uncovers that OTUB1 deubiquitinates and stabilizes CHK1, which enhances CHK1 stability, thereby regulating DNA damage and repair. Additionally, we identify CHK1 as the primary downstream effector responsible for mediating the functional effects exerted by OTUB1 specifically in lung cancer. Importantly, OTUB1 has the potential to be a valuable marker for improving the efficacy of radiotherapy for lung adenocarcinoma.

CONCLUSIONS:

These findings unveil a novel role for OTUB1 in enhancing radioresistance by deubiquitination and stabilizing the expression of CHK1 in lung cancer and indicate that targeting OTUB1 holds great potential as an effective therapeutic approach for enhancing the efficacy of radiotherapy in lung cancer.

项与 OTUD1 相关的新闻（医药）

2024-02-19

·生物探索

Nat Commun | 武汉大学李枫/张蔚/熊洁揭示聚集体的形成促进卵巢癌中ASK1/JNK信号的激活和干性维持

引言聚集体是蛋白质错误折叠聚集的产物，其存在与癌症患者的不良预后相关。然而，聚集体在肿瘤发生和进展中的确切作用仍然未知。2024年2月13日，武汉大学李枫、张蔚及熊洁共同通讯在Nature Communications发表题为“Aggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer”的研究论文，本研究多组学筛选揭示了OTUD1蛋白在保留卵巢癌干细胞（OCSC）特性方面发挥重要作用。从机制上讲，OTUD1蛋白水平升高导致基于OTUD1的细胞质聚集体的形成，该聚集体由位于固有无序OTUD1 N末端区域的短肽介导。此外，基于OTUD1的聚集体通过蛋白质-蛋白质相互作用募集ASK1，进而以非泛素化酶非依赖性方式稳定ASK1，并激活下游JNK信号通路以维持OCSC。值得注意的是，破坏基于OTUD1的聚集体或用ASK1/JNK抑制剂治疗，可有效降低OTUD1high卵巢癌细胞的OCSC干性(OSCS)。该研究表明肿瘤细胞中的聚集体形成可以作为信号转导枢纽，并且基于聚集体的治疗对于OTUD1high的卵巢癌患者具有转化潜力。上皮性卵巢癌是妇科恶性肿瘤相关死亡的主要原因。高级别浆液性卵巢癌（HGSOC）是临床上最常见的组织型，被认为起源于输卵管。尽管初始治疗方法通常有效，但大约80% 的患者会出现复发，复发性疾病的治疗方案仍然具有挑战性。卵巢癌干细胞（OCSC）的存在历来被认为在初始化疗后的致瘤性、肿瘤转移和癌症复发中起着重要作用。消除癌症干细胞（CSC）被认为是癌症治疗的有效策略，促使了解 CSC 亚群如何在肿瘤中维持。与正常干细胞类似，肿瘤干细胞具有自我更新和分化为异质性肿瘤细胞的能力。自我更新和分化之间的平衡有助于 CSC 的丰富性。一些表面标记，如CD44, CD133, CD24, ALDH和EpCAM，已被报道可识别或分离OCSCs。此外，包括NANOG、OCT4和SOX2在内的几个转录因子被认为是细胞内的标志物。在OCSCs向非致瘤性细胞的转化过程中，某些基因的表达是否发生了必要的改变仍然是很大程度上未知的。鉴于卵巢CSC亚群可以通过不同的信号通路维持，因此阐明其激活的机制将提供有价值的诊断生物标志物和治疗靶点。传统化疗和OCSC靶向治疗的结合可能是卵巢癌的一种有效且有前途的抗癌治疗方法。抗OCSC治疗的靶点是调节OSCS维持的OCSC的表面和细胞内标志物。WNT、Hedgehog、Notch、JNK和MAPK等信号通路的激活也被证明与OCSC的特性相关，靶向这些信号通路似乎是一个合适的选择。遗憾的是，不同通路抑制剂单药或联合其他抗癌药物的抗OSCS活性的临床试验迄今没有显示出令人满意的疗效。治疗效果不佳的主要原因之一是无法耐受的毒性。模式图（Credit: Nature Communications）该研究发现去泛素化酶OTUD1被证明对卵巢细胞干性维持很重要。OTUD1高表达与卵巢癌患者不良预后相关。研究进一步表明，OTUD1通过其N端固有无序区域的相互作用在细胞质中形成了蛋白聚集体样的细胞器；这些细胞器隔离ASK1并促进其稳定性，进而激活下游JNK信号通路以维持OSCS的维持。这些发现揭示了聚集体的形成有助于OSCS，并在癌症进展和复发中发挥重要作用。该研究表明肿瘤细胞中的聚集体形成可以作为信号枢纽发挥作用，并且基于聚集体的治疗对于OTUD1high的卵巢癌患者具有转化潜力。原文链接https://doi.org/10.1038/s41467-024-45698-x责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

2023-05-24

·生物谷

科学家揭示了心肌细胞促进病理性心脏重构和功能障碍的机制

高血压的患病率在全球范围内正在上升。超过30%的成年人患有高血压，高血压是中风、心肌梗死和心力衰竭的主要危险因素。高血压患者的左心室负荷长期增加，导致左心室重构、松弛功能受损和心力衰竭风险增加。高血压的患病率在全球范围内正在上升。超过30%的成年人患有高血压，高血压是中风、心肌梗死和心力衰竭的主要危险因素。高血压患者的左心室负荷长期增加，导致左心室重构、松弛功能受损和心力衰竭风险增加。肾素-血管紧张素系统(RAS)被认为是高血压心脏重构的关键介质，其特征是心室肥厚、心脏炎症和纤维化。然而，靶向RAS受体阻滞剂并不能完全逆转心脏重构和心力衰竭。其他治疗方式也有局限性。因此，识别与心力衰竭相关的调节分子并阐明其作用机制具有重要的临床价值。图片来源：https://pubmed.ncbi.nlm.nih.gov/37153745/ 近日，来自杭州医学院的研究者们在Theranostics杂志上发表了题为“OTUD1 promotes pathological cardiac remodeling and heart failure by targeting STAT3 in cardiomyocytes”的文章，该研究揭示了心肌细胞OTUD1通过去泛素化STAT3促进病理性心脏重构和功能障碍。这些研究强调了OTUD1在高血压心力衰竭中的一个新作用，并确认STAT3是OTUD1调节这些作用的靶标。了解心脏恶性重构的分子机制对心力衰竭治疗的发展具有重要意义。最近的研究强调了脱泛素酶在心脏病理生理学中的作用。在本研究中，研究者筛选了心脏重塑实验模型中去泛素酶的变化，这表明了OTU结构域包含蛋白1(OTUD1)的潜在作用。研究者采用野生型或OTUD1基因敲除小鼠慢性血管紧张素II注射和横动脉缩窄(TAC)建立心脏重塑和心力衰竭模型。研究者们还利用AAV9载体在小鼠心脏中过表达了OTUD1，以验证OTUD1的功能。用LC-MS/MS分析结合Co-IP鉴定OTUD1的相互作用蛋白和底物。研究者发现，慢性给予血管紧张素II后，小鼠心脏组织中的OTUD1水平升高。OTUD1基因敲除小鼠对血管紧张素II诱导的心功能障碍、肥大、纤维化和炎症反应具有显著的保护作用。在TAC模型中也得到了类似的结果。从机制上讲，OTUD1结合到STAT3的SH2结构域，并导致STAT3的去泛素化。OTUD1第320位半胱氨酸通过K63去泛素化促进STAT3的磷酸化和核转位，从而增加STAT3的活性，从而诱导心肌细胞的炎症反应、纤维化和肥大。最后，AAV9载体过表达OTUD1可增加Ang II诱导的小鼠心脏重构，阻断STAT3可抑制OTUD1调节的反应。血管紧张素转换酶II介导的心肌肥大和纤维化模型中OTUD1的诱导图片来源：https://pubmed.ncbi.nlm.nih.gov/37153745/ 总之，目前的研究发现，在Ang II攻击的高血压性心功能不全模型中，OTUD1上调，并表明当OTUD1被敲除时，Ang II和TAC诱导的心肌肥大、纤维化和功能缺陷基本上被预防。相反，OTUD1的表达增加加强了Ang II诱导的心脏损伤。在机制研究中，研究者确定STAT3是一个重要的OTUD1底物。研究者将SH2结构域定位在STAT3上作为OTUD1的结合位点，结果表明OTUD1去泛素化STAT3可以增加p-STAT3的水平和STAT3的核转位。这些研究发现，OTUD1通过直接调节STAT3活性，在高血压心脏病中起重要作用。（生物谷 Bioon.com）参考文献 Mengyang Wang et al. OTUD1 promotes pathological cardiac remodeling and heart failure by targeting STAT3 in cardiomyocytes. Theranostics. 2023 Apr 17;13(7):2263-2280. doi: 10.7150/thno.83340.

2022-09-09

·生物谷

《细胞研究》：苏州大学团队破解抑郁症损害免疫系统之谜！

随着近年来人民生活质量的提升，人们在追求丰富物质生活的同时也越来越关注精神的健康。抑郁症作为一种常见的精神性疾病也走入了大家的视野。随着近年来人民生活质量的提升，人们在追求丰富物质生活的同时也越来越关注精神的健康。抑郁症作为一种常见的精神性疾病也走入了大家的视野。抑郁症是一种常见于成年人，并且能显著降低患者生活质量的一种精神性疾病。长期处于抑郁状态的人们生活焦虑，精神萎靡，并且伴随着机体免疫力下降。据统计，大约有15%的重度抑郁患者最终因不能忍受这种状态而选择自杀[1-2]。抑郁症患者经常会伴随着很多身体疾病，但是目前很少有对这两者之间的关系进行研究报道[3]。近日，来自苏州大学生命科学医学研究院郑慧教授课题组和神经科学研究所徐兴顺教授课题组合作回答了为什么抑郁患者更容易被病毒感染。相关研究已发表在Cell Research杂志。这项研究揭示了抑郁诱导的抗病毒免疫功能障碍的详细机制，加深了人们对抑郁症患者更容易被病毒感染的高敏感性的理解。论文首页[4] 之前有研究表明抑郁症与下丘脑和垂体中Abelson helper整合位点1（AHI1）表达相关[5]。且AHI1主要表达在巨噬细胞、上皮细胞以及成纤维细胞上。研究人员发现，重度抑郁症患者（MDD）比健康人的外周血单个核细胞（PBMC）中AHI1的mRNA表达更低，这种现象在巨噬细胞上更加明显。该结果也在使用限制空间的抑郁小鼠模型中得到了验证。那巨噬细胞上AHI1表达降低对免疫功能有什么影响呢？在Ahi1缺陷的小鼠模型中，研究人员观察到干扰素诱导家族因子（ISGs）显著下调表达。因此，研究人员推测Ahi1缺陷的细胞抗病毒能力会受到影响。随后研究人员通过病毒感染Ahi1敲除的小鼠模型实验验证了以上猜测。缺失Ahi1表达的巨噬细胞在被病毒感染时会丧失对病毒的抵抗能力。前面的测序结果已经表明，AhI1缺失会造成ISGs信号下调。研究人员进一步探索了AhI1与ISGs之间更加详细的分子机制。有文献表明Tyk2、JAK1等都是传递IFN-I信号活化的初始调控单元[6]。于是研究人员检测了AhI1沉默后的巨噬细胞中IFN-I信号通路相关分子JAK1、STAT1、STAT2以及Tyk2的变化，发现只有Tyk2的蛋白表达显著降低。这表明AHI1可以调节细胞中Tyk2蛋白的表达水平。研究人员使用脉冲追踪测定法来分析AHI1对Tyk2蛋白稳定性的影响，结果显示巨噬细胞中缺失AHI1会加速Tyk2蛋白的降解。进一步，研究人员在抑郁小鼠模型中也观察到Tyk2表达降低。并且在MDD患者的外周血单核细胞中也发现相同的现象。这些发现表明，抑郁小鼠和人类的AHI1表达降低会影响Tyk2蛋白稳定性以及随后的IFN-I信号传导活性。 AHI1调节Tyk2蛋白稳定性，研究人员猜想AHI1可能会影响Tyk2的泛素化修饰。实验结果显示，广谱去泛素化酶抑制剂PR-619完全抵消了AHI1介导的Tyk2蛋白水平上调。通过对潜在的与AHI1相互作用蛋白的质谱分析，研究人员注意到了去泛素酶OTUD1。OTUD1敲除显著抑制了AHI1介导的Tyk2蛋白水平表达的上调，进一步分析显示，OTUD1以AHI1依赖性方式调节K48连接的Tyk2泛素化。下丘脑-垂体-肾上腺系统（HPA）对于抑郁的调节具有关键作用。已有研究表明精氨酸加压素（AVP）在抑郁症患者中表达上调[8]。有趣的是，研究人员发现，在原代巨噬细胞中精氨酸加压素诱导的Tyk2蛋白表达降低是依赖于AHI1的。于是，研究人员猜想高水平的精氨酸加压素可以降低AHI1以及Tyk2的表达，从而抑制IFN-I信号及抗病毒免疫活性。为了验证以上猜想，研究人员使用剂量为50ng/kg的精氨酸加压素进行小鼠给药实验。结果显示，给药后的小鼠外周血单核细胞中的AHI1的表达水平及脾脏中的Tyk2蛋白表达水平与对照组相比显著降低。同时给药后的小鼠外周血单核细胞中的ISGs信号（lfit1, Rsad2, Mx1）也均显著降低。也就是说，抑郁通过精氨酸加压素下调AHI1的表达从而降低机体的抗病毒免疫应答能力。因此如何能够提高AHI1的表达水平就显得至关重要。通过对一些临床药物的筛选，研究人员注意到止痛药美普他酚（Meptazinol）可以显著促进原代巨噬细胞中的Ahi1 mRNA表达。使用美普他酚处理两种巨噬细胞系，均能显著促进AHI1和Tyk2剂量依赖性表达增加。而AHI1敲除之后又会下调Tyk2的表达水平。通过对抑郁小鼠模型的持续两天的（10mg/kg）的给药，研究人员发现相比未处理的小鼠，实验组小鼠的多脏器中AHI1和Tyk2的蛋白水平均显著升高。而当实验组小组受到病毒感染时，美普他酚显著上调了模型鼠中脾脏和肺脏的ISGs表达水平，抑制了病毒感染。总的来说，研究人员发现了抑郁症患者免疫下降的机制，并证实了美普他酚可以改善IFN-I信号传导并补救抑郁小鼠模型的抗病毒免疫。由于抑郁症患者处于病毒感染的高风险，感染病毒后又会进一步加剧疾病进展。因此，研究人员的发现可以为减轻抑郁患者的症状和改善其生活质量提供帮助。参考文献： [1] ALVAREZ RETUERTO A I, CANTOR R M, GLEESON J G, et al. Association of common variants in the Joubert syndrome gene (AHI1) with autism [J]. Hum Mol Genet, 2008, 17(24): 3887-96. [2] GUZE S B, ROBINS E. Suicide and primary affective disorders [J]. Br J Psychiatry, 1970, 117(539): 437-8. [3] MOUSSAVI S, CHATTERJI S, VERDES E, et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys [J]. Lancet, 2007, 370(9590): 851-8. [4] ZHANG H G, WANG B, YANG Y, et al. Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis [J]. Cell Res, 2022. [5] XU X, YANG H, LIN Y F, et al. Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype [J]. Proc Natl Acad Sci U S A, 2010, 107(44): 19126-31. [6] LUO Q, WU X, ZHAO P, et al. OTUD1 Activates Caspase-Independent and Caspase-Dependent Apoptosis by Promoting AIF Nuclear Translocation and MCL1 Degradation [J]. Adv Sci (Weinh), 2021, 8(8): 2002874. [7] ZHANG L, LIU J, QIAN L, et al. Induction of OTUD1 by RNA viruses potently inhibits innate immune responses by promoting degradation of the MAVS/TRAF3/TRAF6 signalosome [J]. PLoS Pathog, 2018, 14(5): e1007067. [8] VAN LONDEN L, GOEKOOP J G, VAN KEMPEN G M, et al. Plasma levels of arginine vasopressin elevated in patients with major depression [J]. Neuropsychopharmacology, 1997, 17(4): 284-92.