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The concealed side of caspases: beyond a killer of cells. 半胱天冬酶隐藏的一面:超越细胞杀手。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-03 DOI: 10.1007/s00018-024-05495-7
Lina Abdelghany, Chanin Sillapachaiyaporn, Boris Zhivotovsky

Since the late 20th century, researchers have known that caspases are a pillar of cell death, particularly apoptosis. However, recent advances in cell biology have unraveled the multiple roles of caspases. These enzymes have an unconventional role in cell proliferation, differentiation, and invasion. As a result, caspase deregulation can fuel the fire of cancer, incite flames of inflammation, flare neurodegenerative disorders, and exacerbate skin pathologies. Several therapeutic approaches toward caspase inhibition have been investigated, but can caspase inhibitors harness the maladaptive effect of these proteases without causing significant side effects? A few studies have exploited caspase induction for cancer or adoptive cell therapies. Here, we provide a compelling picture of caspases, starting with their evolution, their polytomous roles beyond cell death, the flaws of their deregulation, and the merits of targeting them for therapeutic implications. Furthermore, we provide a deeper understanding of the evolution of caspase-related research up to the current era, pinpointing the role of caspases in cell survival and aiding in the development of effective caspase-targeted therapies.

自20世纪末以来,研究人员已经知道半胱天冬酶是细胞死亡,特别是细胞凋亡的支柱。然而,细胞生物学的最新进展揭示了半胱天冬酶的多重作用。这些酶在细胞增殖、分化和侵袭中起着非常规的作用。因此,解除半胱天冬酶的管制可以助长癌症的火焰,激起炎症的火焰,引发神经退行性疾病,并加剧皮肤病变。已经研究了几种针对半胱天冬酶抑制的治疗方法,但是半胱天冬酶抑制剂能否在不引起明显副作用的情况下利用这些蛋白酶的不适应效应?一些研究利用半胱天冬酶诱导癌症或过继细胞治疗。在这里,我们提供了一幅引人注目的半胱天冬酶的图片,从它们的进化开始,它们在细胞死亡之外的多染色体作用,它们放松管制的缺陷,以及靶向治疗它们的优点。此外,我们对caspase相关研究的发展有了更深入的了解,指出了caspase在细胞存活中的作用,并帮助开发有效的caspase靶向治疗。
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引用次数: 0
Heterogeneous neutrophils in lung transplantation and proteolytic CXCL8 activation in COVID-19, influenza and lung transplant patient lungs. 肺移植患者肺中的异质中性粒细胞和COVID-19、流感和肺移植患者肺中的蛋白水解CXCL8激活。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-03 DOI: 10.1007/s00018-024-05500-z
Seppe Cambier, Fabio Beretta, Amber Nooyens, Mieke Metzemaekers, Noëmie Pörtner, Janne Kaes, Ana Carolina de Carvalho, Emanuela E Cortesi, Hanne Beeckmans, Charlotte Hooft, Mieke Gouwy, Sofie Struyf, Rafael E Marques, Laurens J Ceulemans, Joost Wauters, Bart M Vanaudenaerde, Robin Vos, Paul Proost

Elevated neutrophil counts in broncho-alveolar lavage (BAL) fluids of lung transplant (LTx) patients with chronic lung allograft dysfunction (CLAD) are associated with disease pathology. However, phenotypical characteristics of these cells remained largely unknown. Moreover, despite enhanced levels of the most potent human neutrophil-attracting chemokine CXCL8 in BAL fluid, no discrimination had been made between natural NH2-terminally truncated CXCL8 proteoforms, which exhibit up to 30-fold differences in biological activity. Therefore, we aimed to characterize the neutrophil maturation and activation state, as well as proteolytic activation of CXCL8, in BAL fluids and peripheral blood of LTx patients with CLAD or infection and stable LTx recipients. Flow cytometry and microscopy revealed a high diversity in neutrophil maturity in blood and BAL fluid, ranging from immature band to hypersegmented aged cells. In contrast, the activation phenotype of neutrophils in BAL fluid was remarkably homogeneous. The highly potentiated NH2-terminally truncated proteoforms CXCL8(6-77), CXCL8(8-77) and CXCL8(9-77), but also the partially inactivated CXCL8(10-77), were detected in BAL fluids of CLAD and infected LTx patients, as well as in COVID-19 and influenza patient cohorts by tandem mass spectrometry. Moreover, the most potent proteoform CXCL8(9-77) specifically correlated with the neutrophil counts in the LTx BAL fluids. Finally, rapid proteolysis of CXCL8 in BAL fluids could be inhibited by a combination of serine and metalloprotease inhibitors. In conclusion, proteolytic activation of CXCL8 promotes neutrophilic inflammation in LTx patients. Therefore, application of protease inhibitors may hold pharmacological promise for reducing excessive neutrophil-mediated inflammation and collateral tissue damage in the lungs.

慢性同种异体肺移植功能障碍(chronic lung allograft dysfunction, CLAD)患者肺移植(LTx)患者支气管肺泡灌洗液(BAL)中中性粒细胞计数升高与疾病病理相关。然而,这些细胞的表型特征在很大程度上仍然未知。此外,尽管BAL液中最有效的人类中性粒细胞吸引趋化因子CXCL8水平提高,但天然nh2末端截断的CXCL8蛋白形态之间没有区别,其生物活性差异高达30倍。因此,我们的目的是表征中性粒细胞的成熟和激活状态,以及CXCL8的蛋白水解激活,BAL液和外周血的LTx患者或感染和稳定的LTx受体。流式细胞术和显微镜显示,血液和BAL液中中性粒细胞的成熟度具有高度的多样性,从未成熟的带状细胞到超分割的衰老细胞不等。相比之下,BAL液中中性粒细胞的活化表型明显均匀。采用串联质谱法,检测出了高增强nh2末端截断的蛋白形态CXCL8(6-77)、CXCL8(8-77)和CXCL8(9-77),以及部分失活的CXCL8(10-77),分别存在于CLAD和LTx感染患者以及COVID-19和流感患者的BAL液中。此外,最有效的蛋白形态CXCL8(9-77)与LTx BAL液中的中性粒细胞计数特异性相关。最后,丝氨酸和金属蛋白酶抑制剂联合使用可抑制BAL液中CXCL8的快速蛋白水解。综上所述,CXCL8的蛋白水解激活促进了LTx患者的中性粒细胞炎症。因此,蛋白酶抑制剂的应用可能具有减少过度中性粒细胞介导的炎症和肺部侧支组织损伤的药理学前景。
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引用次数: 0
Potential compensatory mechanisms preserving cardiac function in myotubular myopathy. 维持肌小管肌病心功能的潜在代偿机制。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-03 DOI: 10.1007/s00018-024-05512-9
Alix Simon, Nadège Diedhiou, David Reiss, Marie Goret, Erwan Grandgirard, Jocelyn Laporte

X-Linked myotubular myopathy (XLMTM) is characterized by severe skeletal muscle weakness and reduced life expectancy. The pathomechanism and the impact of non-muscular defects affecting survival, such as liver dysfunction, are poorly understood. Here, we investigated organ-specific effects of XLMTM using the Mtm1-/y mouse model. We performed RNA-sequencing to identify a common mechanism in different skeletal muscles, and to explore potential phenotypes and compensatory mechanisms in the heart and the liver. The cardiac and hepatic function and structural integrity were assessed both in vivo and in vitro. Our findings revealed no defects in liver function or morphology. A disease signature common to several skeletal muscles highlighted dysregulation of muscle development, inflammation, cell adhesion and oxidative phosphorylation as key pathomechanisms. The heart displayed only mild functional alterations without obvious structural defects. Transcriptomic analyses revealed an opposite dysregulation of mitochondrial function, cell adhesion and beta integrin trafficking pathways in cardiac muscle compared to skeletal muscles. Despite this dysregulation, biochemical and cellular experiments demonstrated that these pathways were strongly affected in skeletal muscle and normal in cardiac muscle. Moreover, biomarkers reflecting the molecular activity of MTM1, such as PtdIns3P and dynamin 2 levels, were increased in the skeletal muscles but not in cardiac muscle. Overall, these data suggest a compensatory mechanism preserving cardiac function, pointing to potential therapeutic targets to cure the severe skeletal muscle defects in XLMTM.

x连锁肌小管肌病(XLMTM)的特征是严重的骨骼肌无力和预期寿命缩短。病理机制和非肌肉缺陷影响生存的影响,如肝功能障碍,知之甚少。在这里,我们使用Mtm1-/y小鼠模型研究了XLMTM的器官特异性效应。我们进行了rna测序,以确定不同骨骼肌的共同机制,并探索心脏和肝脏的潜在表型和代偿机制。在体内和体外评估心脏和肝脏功能和结构完整性。我们的研究结果显示肝脏功能和形态没有缺陷。几种骨骼肌共同的疾病特征突出了肌肉发育失调、炎症、细胞粘附和氧化磷酸化是关键的病理机制。心脏仅表现出轻微的功能改变,无明显的结构缺陷。转录组学分析显示,与骨骼肌相比,心肌的线粒体功能、细胞粘附和β整合素运输途径存在相反的失调。尽管存在这种失调,生化和细胞实验表明,这些通路在骨骼肌中受到强烈影响,在心肌中正常。此外,反映MTM1分子活性的生物标志物,如PtdIns3P和dynamin 2水平,在骨骼肌中升高,而在心肌中没有升高。总的来说,这些数据提示了一种维持心脏功能的代偿机制,指出了治疗XLMTM严重骨骼肌缺陷的潜在治疗靶点。
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引用次数: 0
Regulation of neuronal fate specification and connectivity of the thalamic reticular nucleus by the Ascl1-Isl1 transcriptional cascade. Ascl1-Isl1转录级联对丘脑网状核神经元命运规范和连通性的调节。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-03 DOI: 10.1007/s00018-024-05523-6
Quy-Hoai Nguyen, Hong-Nhung Tran, Yongsu Jeong

The thalamic reticular nucleus (TRN) is an anatomical and functional hub that modulates the flow of information between the cerebral cortex and thalamus, and its dysfunction has been linked to sensory disturbance and multiple behavioral disorders. Therefore, understanding how TRN neurons differentiate and establish connectivity is crucial to clarify the basics of TRN functions. Here, we showed that the regulatory cascade of the transcription factors Ascl1 and Isl1 promotes the fate of TRN neurons and concomitantly represses the fate of non-TRN prethalamic neurons. Furthermore, we found that this cascade is necessary for the correct development of the two main axonal connections, thalamo-cortical projections and prethalamo-thalamic projections. Notably, the disruption of prethalamo-thalamic axons can cause the pathfinding defects of thalamo-cortical axons in the thalamus. Finally, forced Isl1 expression can rescue disruption of cell fate specification and prethalamo-thalamic projections in in vitro primary cultures of Ascl1-deficient TRN neurons, indicating that Isl1 is an essential mediator of Ascl1 function in TRN development. Together, our findings provide insights into the molecular mechanisms for TRN neuron differentiation and circuit formation.

丘脑网状核(TRN)是调节大脑皮层和丘脑之间信息流动的解剖和功能中枢,其功能障碍与感觉障碍和多种行为障碍有关。因此,了解TRN神经元如何分化和建立连接对于阐明TRN功能的基础至关重要。在这里,我们发现转录因子Ascl1和Isl1的调控级联促进TRN神经元的命运,并同时抑制非TRN的丘脑前神经元的命运。此外,我们发现这种级联对于两个主要轴突连接,丘脑-皮质投射和丘脑-丘脑前庭投射的正确发展是必要的。值得注意的是,丘脑前-丘脑轴突的破坏可导致丘脑丘脑-皮质轴突的寻路缺陷。最后,在体外原代培养缺乏Ascl1的TRN神经元中,强迫Isl1表达可以挽救细胞命运规范和丘脑-丘脑前投射的破坏,这表明Isl1是Ascl1功能在TRN发育中的重要介质。总之,我们的发现为TRN神经元分化和电路形成的分子机制提供了见解。
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引用次数: 0
Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases. 不同神经退行性疾病中细胞外囊泡分子货物的共同和不同变化。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-03 DOI: 10.1007/s00018-024-05522-7
Anna F Wiersema, Alyssa Rennenberg, Grace Smith, Suzy Varderidou-Minasian, R Jeroen Pasterkamp

Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.

神经退行性疾病,如阿尔茨海默病(AD)、肌萎缩侧索硬化症(ALS)和帕金森病(PD)影响着全世界数百万人。对这些神经退行性疾病的治疗仍然缺乏,因此迫切需要进一步了解其原因和进展。细胞外囊泡(EVs)是一种纳米大小的囊泡,装载着细胞释放的货物,如蛋白质和mirna,在细胞间通讯中起着重要作用。通过EVs的细胞间通讯可以促进病理蛋白的传播,如淀粉样蛋白- β和tau,或通过其他机制引起发病。此外,ev可能作为诊断和监测疾病进展的潜在生物标志物。在这篇综述中,我们总结和讨论了EVs在AD, ALS和PD中的作用的最新进展,重点是每种疾病中的失调货物。我们强调了这些疾病之间共同的失调货物,讨论了潜在的途径,并概述了未来治疗策略的影响。
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引用次数: 0
MTSS1: beyond the integration of actin and membrane dynamics. MTSS1:超越肌动蛋白和膜动力学的整合。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-03 DOI: 10.1007/s00018-024-05511-w
Liudmila Matskova, Shixing Zheng, Elena Kashuba, Ingemar Ernberg, Pontus Aspenström

MTSS1 is a ubiquitously expressed intracellular protein known mainly for its involvement in basic cellular processes, such as the regulation of actin organization and membrane architecture. MTSS1 has attracted much attention for its role as a tumor suppressor, being absent or expressed at reduced levels in advanced and metastasizing cancers. Occasionally, MTSS1 is, instead, upregulated in metastasis and, in some cases, even in primary tumors. In addition to these well-established functions of MTSS1 linked to its I-BAR- and WH2-domains, the protein is involved in modulating cell-cell contacts, cell differentiation, lipid metabolism, and vesicle formation and acts as a scaffolding protein for several E3 ubiquitin ligases. MTSS1 is classified as a housekeeping protein and is never mutated despite the several pathologic phenotypes linked to its dysregulation. Despite MTSS1's involvement in fundamental signaling pathways, MTSS1 gene ablation is not ubiquitously lethal, although it affects embryonic development. Due to MTSS1´s involvement in many seemingly disparate processes, with many cases lacking mechanistic explanations, we found it timely to review the recent data on MTSS1's role at the cellular level, as well as in health and disease, to direct further studies on this interesting multifunctional protein.

MTSS1是一种普遍表达的细胞内蛋白,主要参与基本细胞过程,如肌动蛋白组织和膜结构的调节。MTSS1作为一种肿瘤抑制因子,在晚期和转移性癌症中缺失或表达水平降低,引起了人们的广泛关注。偶尔,MTSS1在转移中表达上调,在某些情况下,甚至在原发肿瘤中也表达上调。除了这些与I-BAR-和wh2结构域相关的MTSS1已确立的功能外,该蛋白还参与调节细胞间接触、细胞分化、脂质代谢和囊泡形成,并作为几种E3泛素连接酶的支架蛋白。MTSS1被归类为一种管家蛋白,尽管有几种病理表型与其失调有关,但它从未发生突变。尽管MTSS1参与基本信号通路,但MTSS1基因消融并不普遍致命,尽管它会影响胚胎发育。由于MTSS1参与了许多看似不同的过程,许多情况下缺乏机制解释,我们发现及时回顾最近关于MTSS1在细胞水平以及在健康和疾病中的作用的数据,以指导对这种有趣的多功能蛋白的进一步研究。
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引用次数: 0
YTHDF2-dependent m6A modification of FOXO3 mRNA mediates TIMP1 expression and contributes to intervertebral disc degeneration following ROS stimulation. ythdf2依赖的m6A修饰FOXO3 mRNA介导TIMP1表达,并有助于ROS刺激后的椎间盘退变。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-03 DOI: 10.1007/s00018-024-05503-w
Fei Wang, Yifeng Wang, Songou Zhang, Mengyang Pu, Ping Zhou

The accumulation of reactive oxygen species (ROS) significantly contributes to intervertebral disc degeneration (IDD), but the mechanisms behind this phenomenon remain unclear. This study revealed elevated ROS levels in the intervertebral discs (IVDs) of aged mice compared to those of younger mice. The local application of hydrogen peroxide (H2O2) near lumbar discs also induced ROS accumulation and IDD. Isobaric tags for relative and absolute quantitation (iTRAQ) analysis of discs from aged and H2O2-injected mice showed increased levels of YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) and matrix metallopeptidase 1/3/7/9 (MMP1/3/7/9), along with decreased levels of forkhead box O3 (FOXO3) and TIMP1 (tissue inhibitor of metalloproteinases 1). Our experiments indicated that in nucleus pulposus (NP) cells and young mouse IVDs that were not exposed to ROS, FOXO3 recruited histone acetyltransferase CBP (CREB binding protein) and mediator complex subunit 1 (Med1) to activate TIMP1 expression, which inhibited MMP activity and prevented disc degeneration. However, ROS exposure activated YTHDF2 and promoted the degradation of m6A-modified FOXO3 mRNA, impairing FOXO3's ability to activate TIMP1. This degradation exacerbated MMP activity and contributed to the degradation of the IVD extracellular matrix. Notably, administration of the YTHDF2 inhibitor DC-Y13-27 in older and H2O2-treated mice significantly enhanced FOXO3 and TIMP1 expression, reduced MMP activity, and mitigated IVD degeneration. Together, this study uncovers a novel ROS-regulated pathway in IDD, centered on the YTHDF2/FOXO3/TIMP1/MMPs axis, suggesting that targeting YTHDF2 may represent a promising therapeutic strategy for combating the progression of IDD.

活性氧(ROS)的积累显著促进了椎间盘退变(IDD),但这一现象背后的机制尚不清楚。这项研究显示,与年轻小鼠相比,老年小鼠椎间盘(IVDs)中的ROS水平升高。腰椎间盘附近局部应用过氧化氢(H2O2)也可引起ROS积累和IDD。老龄小鼠和注射h2o2的小鼠椎间盘的相对和绝对定量等压标记(iTRAQ)分析显示,YTH n6 -甲基腺苷RNA结合蛋白F2 (YTHDF2)和基质金属肽酶1/3/7/9 (MMP1/3/7/9)水平升高,叉头盒O3 (FOXO3)和TIMP1(金属蛋白酶组织抑制剂1)水平降低。我们的实验表明,在未暴露于ROS的髓核(NP)细胞和年轻小鼠ivd中,FOXO3募集组蛋白乙酰转移酶CBP (CREB结合蛋白)和介质复合物亚基1 (Med1)激活TIMP1表达,从而抑制MMP活性,防止椎间盘退变。然而,ROS暴露激活了YTHDF2,促进了m6a修饰的FOXO3 mRNA的降解,损害了FOXO3激活TIMP1的能力。这种降解加剧了MMP的活性,并导致了IVD细胞外基质的降解。值得注意的是,在老年和h2o2处理的小鼠中给予YTHDF2抑制剂DC-Y13-27,可显著提高FOXO3和TIMP1的表达,降低MMP活性,减轻IVD变性。总之,本研究揭示了IDD中以YTHDF2/FOXO3/TIMP1/MMPs轴为中心的一种新的ros调控通路,表明靶向YTHDF2可能是对抗IDD进展的一种有希望的治疗策略。
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引用次数: 0
FGF receptor kinase inhibitors exhibit broad antiviral activity by targeting Src family kinases. FGF受体激酶抑制剂通过靶向Src家族激酶表现出广泛的抗病毒活性。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-02 DOI: 10.1007/s00018-024-05502-x
Debora Stefanova, Dominik Olszewski, Mirco Glitscher, Michael Bauer, Luca Ferrarese, Daria Wüst, Eberhard Hildt, Urs F Greber, Sabine Werner

The development of antiviral strategies is a key task of biomedical research, but broad-spectrum virus inhibitors are scarce. Here we show that fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors reduce infection of several cell types with DNA and RNA viruses by blocking early stages of infection, but not viral cell association. Unexpectedly, their antiviral activity was largely independent of FGFR kinase inhibition. RNA profiling showed upregulation of interferon response genes by FGFR inhibitors, but their expression did not correlate with the antiviral activity in infected cells. Using bioinformatics analysis of kinome data, targeted kinase assays, siRNA-mediated knock-down and pharmacological inhibition experiments, we show that blockade of Src family kinases, in particular Lyn, is mainly responsible for the antiviral activity of FGFR inhibitors. These results identify FGFR inhibitors as broad-spectrum antiviral agents and suggest the poorly studied Lyn kinase as a promising target for the treatment of viral infections.

抗病毒策略的开发是生物医学研究的关键任务,但广谱病毒抑制剂很少。在这里,我们表明成纤维细胞生长因子受体(FGFR)酪氨酸激酶抑制剂通过阻断早期感染而不是病毒细胞关联来减少几种细胞类型与DNA和RNA病毒的感染。出乎意料的是,它们的抗病毒活性在很大程度上独立于FGFR激酶抑制。RNA谱分析显示FGFR抑制剂可上调干扰素应答基因,但其表达与感染细胞的抗病毒活性无关。通过对kinome数据的生物信息学分析、靶向激酶测定、sirna介导的敲除和药理学抑制实验,我们发现阻断Src家族激酶,特别是Lyn,是FGFR抑制剂抗病毒活性的主要原因。这些结果确定了FGFR抑制剂是广谱抗病毒药物,并表明研究较少的Lyn激酶是治疗病毒感染的有希望的靶点。
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引用次数: 0
Knockout of onecut2 inhibits proliferation and promotes apoptosis of tumor cells through SKP2-mediated p53 acetylation in hepatocellular carcinoma. 在肝细胞癌中,敲除onecut2通过skp2介导的p53乙酰化抑制肿瘤细胞增殖并促进肿瘤细胞凋亡。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-29 DOI: 10.1007/s00018-024-05518-3
Cunjie Li, Yuxin Xiao, Jieling Zhou, Shifeng Liu, Ligang Zhang, Xinran Song, Xinhua Guo, Qifang Song, Jianfu Zhao, Ning Deng

Onecut2 (OC2) plays a vital regulatory role in tumor growth, metastasis and angiogenesis. In this study, we report the regulatory role and specific molecular mechanism of OC2 in the apoptosis of hepatocellular carcinoma (HCC) cells. We found that OC2 knockout via the CRISPR/CAS9 system not only significantly inhibited the proliferation and angiogenesis of HCC cells but also significantly promoted apoptosis. The apoptosis rate of the OC2 knockout HCC cell line reached 30.514%. In a mouse model, the proliferation inhibition rate of tumor cells reached 98.8%. To explore the mechanism of apoptosis, ChIP-Seq and dual-luciferase reporter assays were carried out. The results showed that OC2 could directly bind to the promotor of SKP2 and regulate its expression. Moreover, downregulating the expression of OC2 and SKP2 could release p300, promote the acetylation of p53, increase the expression of p21 and p27, and promote the apoptosis of HCC cells. Moreover, the overexpression of OC2 or SKP2 in the knockout HCC cell line clearly inhibited the acetylation level of p53 and reduced cell apoptosis. This study revealed that OC2 could regulate the apoptosis of HCC cells through the SKP2/p53/p21 axis, which may provide some therapeutic targets for HCC in the clinic.

Onecut2 (OC2)在肿瘤生长、转移和血管生成中起着重要的调节作用。在这项研究中,我们报道了OC2在肝细胞癌(HCC)细胞凋亡中的调节作用和特定的分子机制。我们发现,通过CRISPR/CAS9系统敲除OC2不仅能显著抑制HCC细胞的增殖和血管生成,还能显著促进细胞凋亡。OC2敲除HCC细胞株的凋亡率达到30.514%。在小鼠模型中,肿瘤细胞增殖抑制率达到98.8%。为了探索细胞凋亡的机制,我们进行了ChIP-Seq和双荧光素酶报告基因检测。结果表明,OC2可直接结合SKP2启动子并调控其表达。下调OC2和SKP2的表达可释放p300,促进p53的乙酰化,增加p21和p27的表达,促进HCC细胞凋亡。此外,OC2或SKP2在敲除HCC细胞系中过表达明显抑制p53乙酰化水平,减少细胞凋亡。本研究发现OC2可通过SKP2/p53/p21轴调控HCC细胞的凋亡,这可能为临床治疗HCC提供一些靶点。
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引用次数: 0
Downregulated KLF4, induced by m6A modification, aggravates intestinal barrier dysfunction in inflammatory bowel disease. 由m6A修饰诱导的KLF4下调,加重炎症性肠病的肠屏障功能障碍。
IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-29 DOI: 10.1007/s00018-024-05514-7
Xingchao Zhu, Jiayu Wang, Huan Zhang, Hongqin Yue, Jinghan Zhu, Juntao Li, Kun Wang, Kanger Shen, Kexi Yang, Xia Leng, Qinhua Xi, Tongguo Shi

Background: Krüppel-like factor 4 (KLF4), a transcription factor, is involved in various biological processes. However, the role of KLF4 in regulating the intestinal epithelial barrier (IEB) in inflammatory bowel disease (IBD) and its mechanism have not been extensively studied.

Methods: KLF4 expression in IBD patients and colitis mice was analyzed using Gene Expression Omnibus(GEO) database, immunohistochemistry (IHC) and Western blot. The roles of KLF4 in IEB and colitis symptoms were verified in dextran sulfate sodium (DSS)-induced and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model mice using an adenovirus carrying KLF4 shRNA (shKLF4-Adv). Furthermore, the influence of KLF4 on trans-epithelium electrical resistance (TEER), paracellular permeability, apical junction complex (AJC) protein expression and apoptosis was assessed in vitro and in vivo. MeRIP and RIP assays were used to verify the effects of m6A modification on KLF4 expression.

Results: KLF4 expression was significantly decreased in IBD patients and was negatively associated with inflammatory features. KLF4 deletion aggravated colitis symptoms and IEB injuries by reducing AJC protein expression and increasing apoptosis in mice with colitis. Furthermore, KLF4 transcriptionally regulated the expression of AJC proteins and inhibited apoptosis by reducing cellular ROS levels and proinflammatory cytokine expression. Moreover, we observed that METTL3/ALKBH5/YTHDF2-mediated m6A modification led to a decrease in KLF4 expression in Caco-2 cells. In addition, APTO-253, an inducer of KLF4, exhibited a synergistic effect with mesalazine on IEB function.

Conclusions: Our study demonstrated that KLF4 is a crucial regulator of IEB, suggesting that targeting KLF4 may be a promising therapeutic alternative for IBD.

背景:kr ppel样因子4 (KLF4)是一种转录因子,参与多种生物过程。然而,KLF4在炎症性肠病(IBD)中调节肠上皮屏障(IEB)的作用及其机制尚未得到广泛研究。方法:采用基因表达综合数据库(Gene expression Omnibus, GEO)、免疫组化(immunohistochemistry, IHC)和Western blot分析IBD患者和结肠炎小鼠KLF4的表达。采用携带KLF4 shRNA (shKLF4-Adv)的腺病毒,在葡聚糖硫酸钠(DSS)诱导和2,4,6-三硝基苯磺酸(TNBS)诱导的结肠炎模型小鼠中验证了KLF4在IEB和结肠炎症状中的作用。此外,在体外和体内评估KLF4对跨上皮电阻(TEER)、细胞旁通透性、根尖连接复合体(AJC)蛋白表达和凋亡的影响。MeRIP和RIP实验验证m6A修饰对KLF4表达的影响。结果:KLF4在IBD患者中表达显著降低,且与炎症特征呈负相关。KLF4缺失通过降低结肠炎小鼠AJC蛋白表达和增加细胞凋亡加重结肠炎症状和IEB损伤。此外,KLF4通过转录调控AJC蛋白的表达,并通过降低细胞ROS水平和促炎细胞因子表达抑制细胞凋亡。此外,我们观察到METTL3/ALKBH5/ ythdf2介导的m6A修饰导致caco2细胞中KLF4表达降低。此外,KLF4诱导剂APTO-253与美沙拉嗪对IEB功能有协同作用。结论:我们的研究表明KLF4是IEB的关键调节因子,这表明靶向KLF4可能是IBD的一种有希望的治疗方案。
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Cellular and Molecular Life Sciences
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