ISG15

ISG15
  • 文章类型: Journal Article
    原理:急性肾损伤(AKI)具有相当高的死亡率和发病率,再加上缺乏有效的治疗选择。AKI通常转变为慢性肾病(CKD)并最终导致终末期肾衰竭。在缺血再灌注损伤(IRI)小鼠的肾脏中,干扰素刺激的基因15(ISG15)水平上调,顺铂,或单侧输尿管梗阻(UUO),然而,其在AKI发展和随后的AKI至CKD转变中的作用尚不清楚.方法:用双侧或单侧IRI攻击的Isg15敲除(Isg15KO)小鼠,顺铂,或UUO用于研究其在AKI中的作用。我们建立了ISG15过表达或敲除的细胞模型,并对其进行缺氧-复氧,顺铂,或转化生长因子-β1(TGF-β1)刺激。从AKI模型获得的肾脏RNA-seq数据来自公共数据库和我们的研究,用于检测ISG15及其相关基因的表达谱。此外,分析了来自人肾脏同种异体移植活检和小鼠IRI模型的已发表的单细胞RNA-seq数据,以研究ISG15和I型TGF-β受体(TGFβR1)的表达模式。西方印迹,qPCR,免疫共沉淀,我们进行了免疫组织化学染色试验以验证我们的发现.结果:Isg15KO小鼠IRI-,顺铂-,或UUO诱导的AKI和随后的AKI到CKD转变。在缺氧-复氧中,顺铂或TGF-β1处理的HK-2细胞,敲除ISG15减少刺激诱导的细胞纤维化,而具有修饰能力的ISG15的过表达加剧了细胞纤维化。免疫沉淀实验表明,ISG15促进TGFβR1的ISG化,并抑制其泛素化。此外,TGFβR1基因敲除阻断ISG15对HK-2细胞的纤维化加重作用,而TGFβR1的过度表达在IRI诱导的肾损伤期间消除了ISG15敲除的肾保护作用。结论:ISG15通过促进TGFβR1的ISG化,在AKI的发生和随后的AKI至CKD的转化中起重要作用。
    Rationale: Acute kidney injury (AKI) has substantial rates of mortality and morbidity, coupled with an absence of efficacious treatment options. AKI commonly transits into chronic kidney disease (CKD) and ultimately culminates in end-stage renal failure. The interferon-stimulated gene 15 (ISG15) level was upregulated in the kidneys of mice injured by ischemia-reperfusion injury (IRI), cisplatin, or unilateral ureteral obstruction (UUO), however, its role in AKI development and subsequent AKI-to-CKD transition remains unknown. Methods: Isg15 knockout (Isg15 KO) mice challenged with bilateral or unilateral IRI, cisplatin, or UUO were used to investigate its role in AKI. We established cellular models with overexpression or knockout of ISG15 and subjected them to hypoxia-reoxygenation, cisplatin, or transforming growth factor- β1 (TGF-β1) stimulation. Renal RNA-seq data obtained from AKI models sourced from public databases and our studies, were utilized to examine the expression profiles of ISG15 and its associated genes. Additionally, published single cell RNA-seq data from human kidney allograft biopsies and mouse IRI model were analyzed to investigate the expression patterns of ISG15 and the type I TGF-β receptor (TGFβR1). Western blotting, qPCR, co-immunoprecipitation, and immunohistochemical staining assays were performed to validate our findings. Results: Alleviated pathological injury and renal function were observed in Isg15 KO mice with IRI-, cisplatin-, or UUO-induced AKI and the following AKI-to-CKD transition. In hypoxia-reoxygenation, cisplatin or TGF-β1 treated HK-2 cells, knockout ISG15 reduced stimulus-induced cell fibrosis, while overexpression of ISG15 with modification capacity exacerbated cell fibrosis. Immunoprecipitation assays demonstrated that ISG15 promoted ISGylation of TGFβR1, and inhibited its ubiquitination. Moreover, knockout of TGFβR1 blocked ISG15\'s fibrosis-exacerbating effect in HK-2 cells, while overexpression of TGFβR1 abolished the renal protective effect of ISG15 knockout during IRI-induced kidney injury. Conclusions: ISG15 plays an important role in the development of AKI and subsequent AKI-to-CKD transition by promoting TGFβR1 ISGylation.
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  • 文章类型: Journal Article
    尽管肾细胞癌(RCC)是一种常见的癌症,最常见的病理亚型,肾透明细胞癌(ccRCC),仍然对进展的分子机制知之甚少。此外,干扰素刺激基因15(ISG15)与各种类型的癌症有关;然而,其在ccRCC中的生物学作用尚不清楚。本研究旨在探讨ISG15在ccRCC进展中的作用。ISG15在ccRCC中表达上调,与预后不良有关。RNA序列分析和后续实验表明,ISG15调节IL6/JAK2/STAT3信号传导促进ccRCC增殖,迁移,和入侵。此外,我们的动物实验证实,持续的ISG15敲除降低裸鼠的肿瘤生长速率并促进细胞凋亡。ISG15调节IL6/JAK2/STAT3通路,使其成为ccRCC的潜在治疗靶标和预后生物标志物。
    Although renal cell carcinoma (RCC) is a prevalent type of cancer, the most common pathological subtype, clear cell renal cell carcinoma (ccRCC), still has poorly understood molecular mechanisms of progression. Moreover, interferon-stimulated gene 15 (ISG15) is associated with various types of cancer; however, its biological role in ccRCC remains unclear.This study aimed to explore the role of ISG15 in ccRCC progression.ISG15 expression was upregulated in ccRCC and associated with poor prognosis. RNA sequence analysis and subsequent experiments indicated that ISG15 modulated IL6/JAK2/STAT3 signaling to promote ccRCC proliferation, migration, and invasion. Additionally, our animal experiments confirmed that sustained ISG15 knockdown reduced tumor growth rate in nude mice and promoted cell apoptosis. ISG15 modulates the IL6/JAK2/STAT3 pathway, making it a potential therapeutic target and prognostic biomarker for ccRCC.
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  • 文章类型: Journal Article
    干扰素刺激基因15(ISG15),泛素样蛋白及其结合物与各种人类恶性肿瘤有关。然而,其在卵巢癌进展和转移中的作用尚不清楚。在高级别浆液性卵巢癌(HGSOC)中,腹水是腹膜转移的主要原因。在这项研究中,我们发现HGSOC患者腹水中ISG15蛋白表达显著升高,腹水来源的原发性卵巢癌细胞(POCC),POCC小细胞外囊泡(sEV)以及转移组织。我们的结果表明,ISG15通过减少内体-溶酶体融合来增加腹水衍生POCC的胞吐作用,表明在sEV分泌中起关键作用。Further,ISG15的敲低(KD)导致HGSOC细胞和体内小鼠模型的囊泡分泌显着减少,导致HGSOC细胞迁移和侵袭减少。此外,我们的临床前小鼠模型研究揭示了囊泡ISG15对疾病进展和转移的影响.此外,击倒ISG15或使用ISG15抑制剂,DAP5与卡铂的联合治疗显示出在体外提高铂敏感性并在体内降低肿瘤负荷。我们还发现sEV内的ISG15表达代表了HGSOC患者的有希望的预后标志物。我们的研究结果表明,ISG15是抑制HGSOC进展和转移的潜在治疗靶点,囊泡ISG15表达可能是卵巢癌临床治疗中一个有前途的生物标志物。意义:高级别浆液性卵巢癌(HGSOC)具有较高的发病率和死亡率,但是它的进展和转移仍然知之甚少,迫切需要早期发现和靶向治疗。我们的研究提出了新的发现,暗示ISG15介导的囊泡蛋白在HGSOC的发展和传播中。这些结果为潜在的新分子靶标提供了临床前证据,HGSOC的预后标志物和治疗策略可最终提高患者的生存率。
    The interferon stimulated gene 15 (ISG15), a ubiquitin like protein and its conjugates have been implicated in various human malignancies. However, its role in ovarian cancer progression and metastasis is largely unknown. In high grade serous ovarian cancer (HGSOC), ascites is the major contributor to peritoneal metastasis. In this study, we identified significantly elevated ISG15 protein expression in HGSOC patient ascites, ascites derived primary ovarian cancer cells (POCCs), POCC small extracellular vesicles (sEVs) as well as metastatic tissue. Our results demonstrates that ISG15 increases exocytosis in ascites-derived POCCs by decreasing the endosome-lysosomal fusion, indicating a key role in sEV secretion. Further, knockdown (KD) of ISG15 resulted in a significant decrease in vesicles secretion from HGSOC cells and in vivo mouse models, leading to reduced HGSOC cell migration and invasion. Furthermore, our pre-clinical mouse model studies revealed the influence of vesicular ISG15 on disease progression and metastasis. In addition, knockdown of ISG15 or using the ISG15 inhibitor, DAP5, in combination therapy with carboplatin showed to improve the platinum sensitivity in-vitro and reduce tumour burden in-vivo. We also found that ISG15 expression within sEV represents a promising prognostic marker for HGSOC patients. Our findings suggest that ISG15 is a potential therapeutic target for inhibiting progression and metastasis in HGSOC and that vesicular ISG15 expression could be a promising biomarker in the clinical management of ovarian cancer. Significance: High-grade serous ovarian cancer (HGSOC) has high morbidity and mortality rates, but its progression and metastasis are still poorly understood, and there is an urgent need for early detection and targeted therapies. Our study presents novel findings that implicate ISG15-mediated vesicular proteins in the advancement and spread of HGSOC. These results offer pre-clinical evidence of potential new molecular targets, prognostic markers and therapeutic strategies for HGSOC that could ultimately enhance patient survival.
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  • 文章类型: Journal Article
    背景:癌细胞经常进化出坏死抗性,以克服肿瘤发生过程中的各种生存压力。然而,我们之前已经表明,坏死在头颈部鳞状细胞癌(HNSCC)中普遍存在,并通过DAMPs诱导的坏死周围肿瘤细胞的迁移和侵袭性,导致肿瘤进展和生存率低下.这暗示了一种替代策略,即癌症通过重新编程前侵入性坏死微环境(NME)来应对坏死应激。这里,我们的目的是破译坏死细胞如何塑造NME并影响HNSCC进展。
    方法:我们预先建立的细胞坏死模型和新建立的Dox诱导的瘤内坏死模型均用于研究坏死如何影响HNSCC进展。通过RNA-seq分析周围坏死肿瘤细胞的转录组学改变,并在小鼠和患者样品中的NME中进行验证。凋亡之间的差异DAMPs复合物。坏死,和坏死通过无标记蛋白质组学技术进行分析,然后鉴定和验证坏死凋亡特异性DAMP。使用分子对接模拟ISG15的潜在受体,并通过体外测定进一步验证。然后通过敲除坏死的ISG15释放和RAGE抑制剂FPS-ZM1来阻断ISG15-RAGE轴,并测试对肿瘤进展的影响。最后,我们在HNSCC患者队列中进一步检验了我们的发现.
    结果:坏死性凋亡在通过肿瘤类型依赖性DAMPs释放驱动肿瘤细胞侵袭和淋巴转移中起关键作用。机械上,坏死性DAMPs通过NF-κB和STAT3信号诱导坏死性EMT。此外,坏死和cGAS-STING信号之间的内在协调导致产生一组干扰素刺激基因(ISG),作为HNSCC依赖性坏死DAMPs。其中,ISG15在重新编程NME中发挥了重要作用。然后,我们将RAGE鉴定为细胞外ISG15的新型受体。ISG15释放的阻断或ISG15-RAGE相互作用极大地阻碍了HNSCC中的坏死性凋亡驱动的EMT和淋巴转移。最后,临床病理分析显示ISG15在NME中高表达。广泛的坏死性凋亡和高肿瘤细胞RAGE表达与HNSCC患者的肿瘤进展和低生存率相关。
    结论:我们的数据揭示了一种以前未知的cGAS-ISG15-RAGE依赖的坏死微环境重编程,将坏死应力转化为侵袭力以促进HNSCC细胞播散。通过证明通过坏死-cGAS编排及其通过RAGE的下游信号传导来编程生产ISG15,我们阐明了ISG15在HNSCC进展中的独特作用。靶向此类机器可能具有恢复肿瘤内生存压力和预防HNSCC淋巴转移的治疗潜力。
    BACKGROUND: Cancer cells frequently evolve necroptotic resistance to overcome various survival stress during tumorigenesis. However, we have previously showed that necroptosis is widespread in head and neck squamous cell carcinoma (HNSCC) and contributes to tumor progression and poor survival via DAMPs-induced migration and invasiveness in peri-necroptotic tumor cells. This implicated an alternative strategy that cancers cope with necroptotic stress by reprogramming a pro-invasive necroptotic microenvironment (NME). Here, we aim to decipher how necroptotic cells shape the NME and affect HNSCC progression.
    METHODS: Both our pre-established cellular necroptotic model and newly established Dox-induce intratumoral necroptosis model were used to investigate how necroptosis affect HNSCC progression. Transcriptomic alterations in peri-necroptotic tumor cells were analyzed by RNA-seq and validated in the NME in mice and patients\' samples. The differential DAMPs compositon among apopotosis. Necrosis, and necroptosis were analyzed by label-free proteomic technique, and the necroptosis-specific DAMPs were then identified and validated. The potential receptor for ISG15 were simulated using molecular docking and further validated by in vitro assays. Then the ISG15-RAGE axis was blocked by either knockdown of necroptotic-ISG15 release and RAGE inhibitor FPS-ZM1, and the impact on tumor progression were tested. Last, we further tested our findings in a HNSCC-patients cohort.
    RESULTS: Necroptosis played a crucial role in driving tumor-cell invasiveness and lymphatic metastasis via tumor-type dependent DAMPs-releasing. Mechanistically, necroptotic DAMPs induced peri-necroptotic EMT via NF-κB and STAT3 signaling. Furthermore, intrinsic orchestration between necroptotic and cGAS-STING signaling resulted in producing a group of interferon stimulated genes (ISGs) as HNSCC-dependent necroptotic DAMPs. Among them, ISG15 played an essential role in reprogramming the NME. We then identified RAGE as a novel receptor for extracellular ISG15. Either blockage of ISG15 release or ISG15-RAGE interaction dramatically impeded necroptosis-driven EMT and lymphatic metastasis in HNSCC. Lastly, clinicopathological analysis showed high ISG15 expression in NME. Extensive necroptosis and high tumor-cell RAGE expression correlated with tumor progression and poor survival of HNSCC patients.
    CONCLUSIONS: Our data revealed a previously unknown cGAS-ISG15-RAGE dependent reprogramming of the necroptotic microenvironment which converts the necroptotic stress into invasive force to foster HNSCC-cell dissemination. By demonstrating the programmatic production of ISG15 via necroptosis-cGAS orchestration and its downstream signaling through RAGE, we shed light on the unique role of ISG15 in HNSCC progression. Targeting such machineries may hold therapeutic potential for restoring intratumoral survival stress and preventing lymphatic metastasis in HNSCC.
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  • 文章类型: Journal Article
    端粒,潜在的衰老生物标志物,已知随着香烟烟雾的持续暴露而缩短。为了进一步研究这一过程及其对细胞应激和炎症的影响,我们使用香烟烟雾提取物(CSE)的体外模型,观察了CSE处理后端粒稳定TRF2和POT1基因的下调。hTERT是端粒酶的一个亚基和众所周知的致癌标记,在超过85%的癌症中过度表达,并可能导致吸烟者肺癌的发展。我们还观察到CSE治疗后hTERT和ISG15表达水平的增加,以及通过免疫组织化学染色显示,吸烟者肺组织样本中的蛋白质水平与非吸烟者相比增加。通过定量IFN-γ进一步研究了ISG15过表达的影响,一种由ISG15诱导的炎性蛋白,与不吸烟者相比,在吸烟者中显示出更大的上调。TRF2、POT1、hTERT、与不吸烟者相比,在吸烟者的血液和颊拭子样本中观察到ISG15。这项研究的结果提供了深入了解吸烟导致端粒缩短的机制,以及这可能如何导致炎症和/或肿瘤发生的诱导。这可能会导致吸烟者的合并症。
    Telomeres, potential biomarkers of aging, are known to shorten with continued cigarette smoke exposure. In order to further investigate this process and its impact on cellular stress and inflammation, we used an in vitro model with cigarette smoke extract (CSE) and observed the downregulation of telomere stabilizing TRF2 and POT1 genes after CSE treatment. hTERT is a subunit of telomerase and a well-known oncogenic marker, which is overexpressed in over 85% of cancers and may contribute to lung cancer development in smokers. We also observed an increase in hTERT and ISG15 expression levels after CSE treatment, as well as increased protein levels revealed by immunohistochemical staining in smokers\' lung tissue samples compared to non-smokers. The effects of ISG15 overexpression were further studied by quantifying IFN-γ, an inflammatory protein induced by ISG15, which showed greater upregulation in smokers compared to non-smokers. Similar changes in gene expression patterns for TRF2, POT1, hTERT, and ISG15 were observed in blood and buccal swab samples from smokers compared to non-smokers. The results from this study provide insight into the mechanisms behind smoking causing telomere shortening and how this may contribute to the induction of inflammation and/or tumorigenesis, which may lead to comorbidities in smokers.
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  • 文章类型: Journal Article
    泛素样蛋白ISG15(干扰素-s刺激的g烯15)通过干扰素产生后与蛋白质的缀合(ISG化)来调节宿主对细菌和病毒感染的反应。ISGylation被高度特异性的半胱氨酸蛋白酶USP18拮抗,这是主要的去ISGylating酶。然而,USP18对ISG15异常特异性的潜在机制仍然难以捉摸。这里,我们显示USP18与其旁系USP41相互作用,其催化域与USP18共有97%的同一性.然而,USP41不作为脱ISG酶,这导致我们进行了比较分析,以破译这种差异的基础,揭示USP18对ISG15特异性的分子决定因素。我们发现USP18C末端,以及位置198处的保守亮氨酸,对于其酶活性是必不可少的,并且根据AlphaFold预测可能充当功能表面。最后,我们建议USP41以不依赖催化的方式拮抗来自底物的尚未研究的泛素样蛋白FAT10(HLA-F一种相邻的转录本10)的缀合。总之,我们的结果为USP18对ISG15的特异性提供了新的见解,同时确定USP41是FAT10缀合的负调节因子.
    The ubiquitin-like protein ISG15 (interferon-stimulated gene 15) regulates the host response to bacterial and viral infections through its conjugation to proteins (ISGylation) following interferon production. ISGylation is antagonized by the highly specific cysteine protease USP18, which is the major deISGylating enzyme. However, mechanisms underlying USP18\'s extraordinary specificity towards ISG15 remains elusive. Here, we show that USP18 interacts with its paralog USP41, whose catalytic domain shares 97% identity with USP18. However, USP41 does not act as a deISGylase, which led us to perform a comparative analysis to decipher the basis for this difference, revealing molecular determinants of USP18\'s specificity towards ISG15. We found that USP18 C-terminus, as well as a conserved Leucine at position 198, are essential for its enzymatic activity and likely act as functional surfaces based on AlphaFold predictions. Finally, we propose that USP41 antagonizes conjugation of the understudied ubiquitin-like protein FAT10 (HLA-F adjacent transcript 10) from substrates in a catalytic-independent manner. Altogether, our results offer new insights into USP18\'s specificity towards ISG15, while identifying USP41 as a negative regulator of FAT10 conjugation.
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  • 文章类型: Journal Article
    对病毒的先天免疫应答部分是由干扰素(IFN)诱导的限制因子形成的,包括ISG15、P21和SAMHD1。IFN产生可被ISG15特异性蛋白酶USP18阻断。HIV-1已经进化为规避宿主免疫监视。这种机制可能涉及USP18。在我们最近的研究中,我们证明HIV-1感染诱导USP18,其通过消除p21的抗病毒功能而显著增强HIV-1的复制.USP18通过积累错误折叠的显性阴性p53来下调p21,从而使野生型p53反式激活失活,导致参与从头dNTP生物合成途径和灭活SAMHD1的关键酶上调。尽管USP18介导的感染细胞中HIV-1DNA的增加,有趣的是注意到cGAS-STING介导的对病毒DNA的感知被废除。的确,USP18的表达或ISG15的敲除抑制HIV-1的感知。我们证明STING在残基K224、K236、K289、K347、K338和K370处被ISG化。STINGK289连接的ISG化的抑制抑制其寡聚化和IFN诱导。我们认为人类USP18是一种新的因子,可能以多种方式促进HIV-1复制。
    The innate immune response to viruses is formed in part by interferon (IFN)-induced restriction factors, including ISG15, p21, and SAMHD1. IFN production can be blocked by the ISG15-specific protease USP18. HIV-1 has evolved to circumvent host immune surveillance. This mechanism might involve USP18. In our recent studies, we demonstrate that HIV-1 infection induces USP18, which dramatically enhances HIV-1 replication by abrogating the antiviral function of p21. USP18 downregulates p21 by accumulating misfolded dominant negative p53, which inactivates wild-type p53 transactivation, leading to the upregulation of key enzymes involved in de novo dNTP biosynthesis pathways and inactivated SAMHD1. Despite the USP18-mediated increase in HIV-1 DNA in infected cells, it is intriguing to note that the cGAS-STING-mediated sensing of the viral DNA is abrogated. Indeed, the expression of USP18 or knockout of ISG15 inhibits the sensing of HIV-1. We demonstrate that STING is ISGylated at residues K224, K236, K289, K347, K338, and K370. The inhibition of STING K289-linked ISGylation suppresses its oligomerization and IFN induction. We propose that human USP18 is a novel factor that potentially contributes in multiple ways to HIV-1 replication.
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  • 文章类型: Journal Article
    精确调节核输出对于维持mRNA稳态和影响肿瘤进展至关重要。然而,控制核mRNA输出的机制仍未阐明。在这里,揭示了乳腺癌(BC)中增强的缺氧长非编码RNA(lncRNA前列腺癌相关转录本6(PCAT6)促进m6A修饰的mRNA的核输出,支持乳腺癌干细胞(BCSCs)干性和阿霉素抗性。临床上,低氧PCAT6与恶性BC特征和不良预后相关。机械上,PCAT6充当干扰素刺激基因15(ISG15)和异质核核糖核蛋白A2/B1(hnRNPA2B1)之间的支架,导致hnRNPA2B1的ISG化,从而保护hnRNPA2B1免受泛素化介导的蛋白酶体降解。有趣的是,作为M6A阅读器,hnRNPA2B1通过Aly/REF出口因子(ALYREF)/核RNA出口因子1(NXF1)复合物选择性介导m6A标记的mRNA核出口,这促进了干性相关基因的表达。HnRNPA2B1敲低或mRNA输出抑制可导致保留与干性维持相关的核m6A标记的mRNA,抑制BCSCs自我更新,有效提高阿霉素治疗的疗效。这些发现证明了m6A修饰的mRNA核输出在BC进展中的关键作用,强调抑制m6A标记的mRNA及其核输出是改善癌症化疗的潜在治疗策略。
    Regulating nuclear export precisely is essential for maintaining mRNA homeostasis and impacts tumor progression. However, the mechanisms governing nuclear mRNA export remain poorly elucidated. Herein, it is revealed that the enhanced hypoxic long no-ncoding RNA (lncRNA prostate cancer associated transcript 6 (PCAT6) in breast cancer (BC) promotes the nuclear export of m6A-modified mRNAs, bolstering breast cancer stem cells (BCSCs) stemness and doxorubicin resistance. Clinically, hypoxic PCAT6 correlates with malignant BC features and poor prognosis. Mechanically, PCAT6 functions as a scaffold between interferon-stimulated gene 15 (ISG15) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), leading to ISGylation of hnRNPA2B1, thus protecting hnRNPA2B1 from ubiquitination-mediated proteasomal degradation. Interestingly, as an m6A reader, hnRNPA2B1 selectively mediates m6A-tagged mRNAs nuclear export via the Aly/REF export factor (ALYREF)/ nuclear RNA export factor 1 (NXF1) complex, which promotes stemness-related genes expression. HnRNPA2B1 knockdown or mRNA export inhibition can result in the retention of nuclear m6A-tagged mRNA associated with stemness maintenance, which suppresses BCSCs self-renewal and effectively improves the efficacy of doxorubicin therapy. These findings demonstrate the pivotal role of m6A-modified mRNA nuclear export in BC progression, highlighting that the inhibition of m6A-tagged mRNA and its nuclear export is a potential therapeutic strategy for the amelioration of cancer chemotherapy.
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  • 文章类型: Journal Article
    药物性肝损伤(DILI)是一个重要的全球健康问题,具有很高的死亡率和发病率风险。DILI的一个常见原因是对乙酰氨基酚(APAP)过量。GSDME是诱导非规范焦亡的效应蛋白。在这项研究中,GSDME的激活,但不是GSDMD,据报道,小鼠和患者的肝脏组织中存在APAP-DILI。GSDME的淘汰,而不是GSDMD,在小鼠中保护它们免受APAP-DILI的侵害。肝细胞特异性拯救GSDME的小鼠再现了APAP诱导的肝损伤。此外,在APAP诱导的DILI中观察到的免疫细胞库的改变,例如用单核细胞衍生的KC替换TIM4+常驻Kupffer细胞(KC),Ly6C+单核细胞浸润,MerTk+巨噬细胞消耗,中性粒细胞增加,在肝细胞特异性抢救GSDME的小鼠中再次出现。机械上,APAP暴露导致干扰素刺激基因15(ISG15)的大量损失,导致氨基甲酰磷酸合成酶-1(CPS1)的去ISG化,通过K48连接的泛素化促进其降解,导致氨清除功能障碍。GSDME删除阻止了这些影响。延迟施用富马酸二甲酯抑制GSDME裂解并减轻氨积累,减轻肝损伤。这一发现证明了GSDME在APAP-DILI中通过促进焦凋亡和CPS1去ISG化的先前未表征的作用,表明抑制GSDME可能是APAP-DILI的有希望的治疗选择。
    Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.
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  • 文章类型: Journal Article
    C端结合蛋白1(CtBP1)是许多肿瘤抑制基因的关键转录辅抑制因子,在癌症的发展中起着不同的作用。CtBP1的转录抑制功能是通过招募组蛋白修饰酶来介导的,如组蛋白脱乙酰酶和组蛋白甲基转移酶,通过与DNA相互作用因子结合来靶向基因。已经确定了CtBP1的几个翻译后修饰,包括泛素化,磷酸化,和SUMOylation。本文报导CtBP1由ISG15共轭。在HeLa细胞中干扰素-α处理后,通过ISG15修饰内源性CtBP1。CtBP1的ISG化进程受去ISG化进程USP18和ISG15E3连接酶EFP调控。有趣的是,CtBP1的ISG化影响了CtBP1与CtBP1相关转录复合物的一些组分之间的结合亲和力。HDAC1和LSD1比非缀合的CtBP1更有效地结合ISG15缀合的CtBP1。另一方面,CtBP1和HDAC4之间的结合不受ISG15修饰的影响。此外,ISG15修饰增强了CtBP1对几个与EMT和凋亡相关的靶基因的转录抑制活性。这些发现表明,CtBP1的ISG15修饰调节了CtBP1的功能和活性,CtBP1的ISG化可能为CtBP1介导的癌症提供了新的见解。
    C-terminal binding protein 1 (CtBP1) is a critical transcriptional corepressor of many tumor suppressor genes and plays diverse roles in the progression of cancers. The transcriptional repression function of CtBP1 is mediated by recruiting histone-modifying enzymes, such as histone deacetylases and histone methyltransferases, to target genes by binding with DNA-interacting factors. Several post-translational modifications of CtBP1 have been identified, including ubiquitination, phosphorylation, and SUMOylation. This paper reports that CtBP1 is conjugated by ISG15. Endogenous CtBP1 was modified by ISG15 after interferon-α treatment in HeLa cells. The ISGylation process of CtBP1 was regulated by deISGylation enzyme USP18 and ISG15 E3 ligase EFP. Interestingly, CtBP1 ISGylation affected the binding affinity between CtBP1 and some components of CtBP1-associated transcriptional complexes. HDAC1 and LSD1 bound more efficiently to ISG15-conjugated CtBP1 than non-conjugated CtBP1. On the other hand, binding between CtBP1 and HDAC4 was unaffected by ISG15 modification. Furthermore, ISG15 modification enhanced the transcriptional repression activity of CtBP1 on several target genes related to EMT and apoptosis. These findings suggest that the ISG15 modification of CtBP1 modulates the function and activity of CtBP1 and that CtBP1 ISGylation may provide a new insight for CtBP1-mediated cancers.
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