Deubiquitinating enzymes(DUBs)are key enzymes capable of cleaving ubiquitin chains and synergizing with ubiquitination modifications to regulate the function of key proteins andmaintain normal physiological functions....Deubiquitinating enzymes(DUBs)are key enzymes capable of cleaving ubiquitin chains and synergizing with ubiquitination modifications to regulate the function of key proteins andmaintain normal physiological functions.OTUDs are a key subfamily of the ovarian tumor protease(OTU)family,with important DUB activities,and include mainly OTUD1,OTUD2,OTUD3,OTUD4,OTUD5,OTUD6A,and OTUD6B.In recent years,research on OTUD proteins has been gradually emphasized,and their aberrant expression has demonstrated significant research value in many diseases,such as cancer,immune abnormalities,neurological disorders,and embryonic developmental abnormalities.Therefore,a comprehensive understanding of the regulatory mechanisms of OTUD proteins and their use as therapeutic targets for diseases is of great value.This article focuses on the role of individual OTUD proteins in cancer progression and antiviral response.Importantly,in the context of cancer,we elaborate on their deubiquitinated protein targets and summarize the signaling mechanisms by which they promote or inhibit cancer progression.In the future,targeting OTUD proteins may become a therapeutic direction for cancer,and this review may be useful for research related to OTUD proteins and cancer.At present,there is a lack of research on targeted inhibitors or activators of OTUDs.More in vivo and in vitro studies on OTUDs may contribute to the development of inhibitors or agonists targeting OTUDs.Of course,when conducting these studies,researchers also need to pay attention to the impact of OTUDs on the host’s antiviral immune response.展开更多
PTEN(phosphatase and tension homology,deleted in chromosome 10)是重要的抑癌分子,其蛋白剂量水平的精细变化与肿瘤的发生发展密切相关。PTEN的蛋白水平调控研究一直是该领域的研究热点,虽然已经发现了数个PTEN的泛素连接酶,但能调...PTEN(phosphatase and tension homology,deleted in chromosome 10)是重要的抑癌分子,其蛋白剂量水平的精细变化与肿瘤的发生发展密切相关。PTEN的蛋白水平调控研究一直是该领域的研究热点,虽然已经发现了数个PTEN的泛素连接酶,但能调控PTEN蛋白稳定性的去泛素化酶却一直不明确。该文介绍了PTEN泛素化修饰的最新进展,去泛素化酶OTUD3(OTU domaincontaining protein 3)通过去除PTEN的多聚泛素化维持其蛋白水平,并发挥抑癌功能。这一研究进展弥补了通过拮抗泛素化降解从而稳定PTEN这一长期未被阐释的调控机制。展开更多
目的研究乳腺癌手术切除患者放疗前后外周血单个核细胞中生存素(Survivin)和去泛素化酶3(OUT domain-containing protein 3,OTUD3)mRNA的表达情况及与预后的关系。方法选取79例乳腺癌并行扩大根治术的患者作为观察组,在切除手术后对观...目的研究乳腺癌手术切除患者放疗前后外周血单个核细胞中生存素(Survivin)和去泛素化酶3(OUT domain-containing protein 3,OTUD3)mRNA的表达情况及与预后的关系。方法选取79例乳腺癌并行扩大根治术的患者作为观察组,在切除手术后对观察组患者行为期2个月的放射治疗,另选取同期健康体检志愿者55例作为对照组。检测观察组放疗前后及对照组的外周血单个细胞核中Survivin-mRNA和OTUD3-mRNA表达情况,并且分析其变化及其与疾病预后的关系。结果观察组放疗前后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA的表达量均高于对照组,差异具有统计学意义(P<0.05)。观察组放疗后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA低于放疗前,差异具有统计学意义(P<0.05);检测放疗前后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA的表达情况与年龄、肿瘤大小对比差异无统计学意义(P>0.05),与肿瘤分期、肿瘤分化和淋巴结转移情况对比差异具统计学关系;放疗前后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA的表达量与肿瘤分期都呈现显著正相关关系(γ=0.622,γ=0.684,γ=0.705,γ=0.714;P<0.001);与肿瘤分化呈现显著负相关关系(γ=-0.548,γ=-0.629,γ=-0.574,γ=-0.596;P<0.001);与淋巴结转移呈现显著正相关关系(γ=0.685,γ=0.711,γ=0.697,γ=0.688;P<0.001)。根据ROC曲线获得,最佳界限以Survivin-mRNA(1.67)、OTUD3-mRNA(0.49)可获得ROC曲线下最大面积,两项联合检测结果阳性,表明乳腺癌术后放疗与Survivin-mRNA、OTUD3-mRNA密切相关,且两项联合检测的敏感度(81.0%)、特异度(83.6%)均高于单项检测(P<0.05)。结论监测乳腺癌患者术后体内Survivin-mRNA和OTUD3-mRNA表达情况对术后放疗短期预后存在一定评估价值。因此Survivin-mRNA和OTUD3-mRNA也许能够作为癌症术后放疗评估预后的重要生物指标。展开更多
Acetaminophen(APAP)is the primary cause of drug-induced acute liver failure.Ovarian tumor deubiquitinase 6A(OTUD6A),a recently discovered deubiquitinase of the OTU family,has been primarily studied in tumor contexts.H...Acetaminophen(APAP)is the primary cause of drug-induced acute liver failure.Ovarian tumor deubiquitinase 6A(OTUD6A),a recently discovered deubiquitinase of the OTU family,has been primarily studied in tumor contexts.However,its role in APAP-induced liver injury(AILI)remains unclear.Therefore,this study aimed to investigate the involvement of OTUD6A in the pathogenesis of AILI.Our findings demonstrated a substantial upregulation of OTUD6A in both the liver tissue and isolated hepatocytes of mice following APAP stimulation.OTUD6A knockout exacerbated APAP-induced inflammation,hepatocyte necrosis,and liver injury,whereas OTUD6A overexpression alleviated these pathologies.Mechanistically,OTUD6A directly interacted with the enhancer of zeste homolog 2(EZH2)and selectively removed K48-linked polyubiquitin chains from EZH2,enhancing its stability.This resulted in increased protein levels of EZH2 and H3K27me3,as well as reduced endoplasmic reticulum(ER)stress and cell death in hepatocytes.Collectively,our research uncovers a novel role for OTUD6A in mitigating APAP-induced liver injury by promoting EZH2 stabilization.展开更多
目的去泛素化酶OTUD7B与肿瘤的发生、发展密切相关。为了明确OTUD7B在乳腺癌中所发挥的作用,实验利用慢病毒构建高表达OTUD7B载体感染MCF-7乳腺癌细胞后对其生物学行为的影响。方法构建带有绿色荧光蛋白标签的人OTUD7B表达质粒的慢病毒(...目的去泛素化酶OTUD7B与肿瘤的发生、发展密切相关。为了明确OTUD7B在乳腺癌中所发挥的作用,实验利用慢病毒构建高表达OTUD7B载体感染MCF-7乳腺癌细胞后对其生物学行为的影响。方法构建带有绿色荧光蛋白标签的人OTUD7B表达质粒的慢病毒(pEGFP-hOTUD7B)及对照(pEGFP-CI)感染MCF-7乳腺癌细胞;于荧光倒置显微镜下观察病毒转染效果及应用蛋白质印迹法及免疫组化法检测OTUD7B的表达水平;MTS法检测实验组(pEGFP-hOTUD7B)、阴性对照组(pEGFP-CI)和正常对照组对MCF-7乳腺癌细胞增殖能力的影响;应用细胞划痕实验检测细胞迁移能力;流式细胞仪检测细胞凋亡。结果感染病毒后于荧光倒置显微镜下观察病毒感染效率,可见病毒感染成功。应用蛋白质印迹法检测病毒感染率并找出最适病毒感染复数(multiplicity of infection,MOI),当MOI=30时,实验组、阴性对照组和正常对照组灰度值分别为3.81±0.08、2.12±0.078和2.05±0.15,差异有统计学意义,F=402.03,P<0.001。应用免疫组化法可见感染OTUD7B表达水平。MTS法结果显示,实验组、阴性对照组和正常对照组细胞24hA值分别为0.36±0.08、0.56±0.25和0.69±0.17,F=11.819,P<0.001;48hA值分别为0.65±0.17、1.45±0.48和1.82±0.63,F=23.752,P<0.001;在72hA值分别为0.73±0.21、1.58±0.63和1.99±0.27,F=35.563,P<0.001。细胞划痕试验显示,24h后实验组组迁移率为(7.7±0.91)%,阴性对照组和正常对照组迁移率分别为(13.4±1.52)%和(12.1±1.32)%,F=49.36,P<0.001,48h后实验组迁移率为(12.4±1.29)%,阴性对照组及正常对照组迁移率分别为(32.9±1.71)%和(31.8±1.59)%,F=504.50,P<0.001。流式细胞仪检测细胞凋亡结果提示,实验组与阴性对照组及正常对照组相比明显使细胞阻滞在G_0/G_1期,促进其凋亡,F_(G_0/G_1)期=425.102,F_S期=135.063,均P<0.001。结论成功构建了能够高表达OTUD7B的慢病毒载体,明显抑制了MCF-7乳腺癌细胞增殖、迁移,并促进了其凋亡。展开更多
文摘Deubiquitinating enzymes(DUBs)are key enzymes capable of cleaving ubiquitin chains and synergizing with ubiquitination modifications to regulate the function of key proteins andmaintain normal physiological functions.OTUDs are a key subfamily of the ovarian tumor protease(OTU)family,with important DUB activities,and include mainly OTUD1,OTUD2,OTUD3,OTUD4,OTUD5,OTUD6A,and OTUD6B.In recent years,research on OTUD proteins has been gradually emphasized,and their aberrant expression has demonstrated significant research value in many diseases,such as cancer,immune abnormalities,neurological disorders,and embryonic developmental abnormalities.Therefore,a comprehensive understanding of the regulatory mechanisms of OTUD proteins and their use as therapeutic targets for diseases is of great value.This article focuses on the role of individual OTUD proteins in cancer progression and antiviral response.Importantly,in the context of cancer,we elaborate on their deubiquitinated protein targets and summarize the signaling mechanisms by which they promote or inhibit cancer progression.In the future,targeting OTUD proteins may become a therapeutic direction for cancer,and this review may be useful for research related to OTUD proteins and cancer.At present,there is a lack of research on targeted inhibitors or activators of OTUDs.More in vivo and in vitro studies on OTUDs may contribute to the development of inhibitors or agonists targeting OTUDs.Of course,when conducting these studies,researchers also need to pay attention to the impact of OTUDs on the host’s antiviral immune response.
文摘PTEN(phosphatase and tension homology,deleted in chromosome 10)是重要的抑癌分子,其蛋白剂量水平的精细变化与肿瘤的发生发展密切相关。PTEN的蛋白水平调控研究一直是该领域的研究热点,虽然已经发现了数个PTEN的泛素连接酶,但能调控PTEN蛋白稳定性的去泛素化酶却一直不明确。该文介绍了PTEN泛素化修饰的最新进展,去泛素化酶OTUD3(OTU domaincontaining protein 3)通过去除PTEN的多聚泛素化维持其蛋白水平,并发挥抑癌功能。这一研究进展弥补了通过拮抗泛素化降解从而稳定PTEN这一长期未被阐释的调控机制。
文摘目的研究乳腺癌手术切除患者放疗前后外周血单个核细胞中生存素(Survivin)和去泛素化酶3(OUT domain-containing protein 3,OTUD3)mRNA的表达情况及与预后的关系。方法选取79例乳腺癌并行扩大根治术的患者作为观察组,在切除手术后对观察组患者行为期2个月的放射治疗,另选取同期健康体检志愿者55例作为对照组。检测观察组放疗前后及对照组的外周血单个细胞核中Survivin-mRNA和OTUD3-mRNA表达情况,并且分析其变化及其与疾病预后的关系。结果观察组放疗前后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA的表达量均高于对照组,差异具有统计学意义(P<0.05)。观察组放疗后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA低于放疗前,差异具有统计学意义(P<0.05);检测放疗前后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA的表达情况与年龄、肿瘤大小对比差异无统计学意义(P>0.05),与肿瘤分期、肿瘤分化和淋巴结转移情况对比差异具统计学关系;放疗前后外周血单个核细胞中Survivin-mRNA和OTUD3-mRNA的表达量与肿瘤分期都呈现显著正相关关系(γ=0.622,γ=0.684,γ=0.705,γ=0.714;P<0.001);与肿瘤分化呈现显著负相关关系(γ=-0.548,γ=-0.629,γ=-0.574,γ=-0.596;P<0.001);与淋巴结转移呈现显著正相关关系(γ=0.685,γ=0.711,γ=0.697,γ=0.688;P<0.001)。根据ROC曲线获得,最佳界限以Survivin-mRNA(1.67)、OTUD3-mRNA(0.49)可获得ROC曲线下最大面积,两项联合检测结果阳性,表明乳腺癌术后放疗与Survivin-mRNA、OTUD3-mRNA密切相关,且两项联合检测的敏感度(81.0%)、特异度(83.6%)均高于单项检测(P<0.05)。结论监测乳腺癌患者术后体内Survivin-mRNA和OTUD3-mRNA表达情况对术后放疗短期预后存在一定评估价值。因此Survivin-mRNA和OTUD3-mRNA也许能够作为癌症术后放疗评估预后的重要生物指标。
基金supported by the Medical and Health Science Research Project of Zhejiang Province(2022KY348 to Wei Zuo and 2023XY164 to Lijiang Huang,China)th e Key Research Project of Wenzhou City(ZY2021021 to Yi Wang,China).
文摘Acetaminophen(APAP)is the primary cause of drug-induced acute liver failure.Ovarian tumor deubiquitinase 6A(OTUD6A),a recently discovered deubiquitinase of the OTU family,has been primarily studied in tumor contexts.However,its role in APAP-induced liver injury(AILI)remains unclear.Therefore,this study aimed to investigate the involvement of OTUD6A in the pathogenesis of AILI.Our findings demonstrated a substantial upregulation of OTUD6A in both the liver tissue and isolated hepatocytes of mice following APAP stimulation.OTUD6A knockout exacerbated APAP-induced inflammation,hepatocyte necrosis,and liver injury,whereas OTUD6A overexpression alleviated these pathologies.Mechanistically,OTUD6A directly interacted with the enhancer of zeste homolog 2(EZH2)and selectively removed K48-linked polyubiquitin chains from EZH2,enhancing its stability.This resulted in increased protein levels of EZH2 and H3K27me3,as well as reduced endoplasmic reticulum(ER)stress and cell death in hepatocytes.Collectively,our research uncovers a novel role for OTUD6A in mitigating APAP-induced liver injury by promoting EZH2 stabilization.
文摘目的去泛素化酶OTUD7B与肿瘤的发生、发展密切相关。为了明确OTUD7B在乳腺癌中所发挥的作用,实验利用慢病毒构建高表达OTUD7B载体感染MCF-7乳腺癌细胞后对其生物学行为的影响。方法构建带有绿色荧光蛋白标签的人OTUD7B表达质粒的慢病毒(pEGFP-hOTUD7B)及对照(pEGFP-CI)感染MCF-7乳腺癌细胞;于荧光倒置显微镜下观察病毒转染效果及应用蛋白质印迹法及免疫组化法检测OTUD7B的表达水平;MTS法检测实验组(pEGFP-hOTUD7B)、阴性对照组(pEGFP-CI)和正常对照组对MCF-7乳腺癌细胞增殖能力的影响;应用细胞划痕实验检测细胞迁移能力;流式细胞仪检测细胞凋亡。结果感染病毒后于荧光倒置显微镜下观察病毒感染效率,可见病毒感染成功。应用蛋白质印迹法检测病毒感染率并找出最适病毒感染复数(multiplicity of infection,MOI),当MOI=30时,实验组、阴性对照组和正常对照组灰度值分别为3.81±0.08、2.12±0.078和2.05±0.15,差异有统计学意义,F=402.03,P<0.001。应用免疫组化法可见感染OTUD7B表达水平。MTS法结果显示,实验组、阴性对照组和正常对照组细胞24hA值分别为0.36±0.08、0.56±0.25和0.69±0.17,F=11.819,P<0.001;48hA值分别为0.65±0.17、1.45±0.48和1.82±0.63,F=23.752,P<0.001;在72hA值分别为0.73±0.21、1.58±0.63和1.99±0.27,F=35.563,P<0.001。细胞划痕试验显示,24h后实验组组迁移率为(7.7±0.91)%,阴性对照组和正常对照组迁移率分别为(13.4±1.52)%和(12.1±1.32)%,F=49.36,P<0.001,48h后实验组迁移率为(12.4±1.29)%,阴性对照组及正常对照组迁移率分别为(32.9±1.71)%和(31.8±1.59)%,F=504.50,P<0.001。流式细胞仪检测细胞凋亡结果提示,实验组与阴性对照组及正常对照组相比明显使细胞阻滞在G_0/G_1期,促进其凋亡,F_(G_0/G_1)期=425.102,F_S期=135.063,均P<0.001。结论成功构建了能够高表达OTUD7B的慢病毒载体,明显抑制了MCF-7乳腺癌细胞增殖、迁移,并促进了其凋亡。
