查看更多>>摘要：Meningioma is one of the most common primary neoplasms in the central nervous system,whereas there is still no specific molec-ularly targeted therapy that has been approved for the clinical treatment of aggressive meningiomas.There is therefore an urgent demand to decrypt the biological and molecular landscape of malignant meningioma.Here,through the in-silica prescreening and 10-year follow-up of 445 meningioma patients,we uncovered that CBX7 is progressively decreased with malignancy grade and neoplasia stage in meningioma and a high CBX7 expression level predicts a favorable prognosis in meningioma patients.CBX7 restoration significantly induces cell cycle arrest and inhibits meningioma cell proliferation.iTRAQ-based proteomics analysis indicated that CBX7 restoration triggers the metabolic shift from glycolysis to oxidative phosphorylation.The mechanistic study demonstrated that CBX7 promotes the proteasome-dependent degradation of c-MYC proteins by transcriptionally inhibiting the expression of a c-MYC deubiquitinase,USP44,which attenuates c-MYC-mediated transactivation of LDHA transcripts and further inhibits glycolysis and subsequent cellular proliferation.More importantly,the functional role of CBX7 was further confirmed in both subcutaneous and orthotopic meningioma xenografts mouse models and human meningioma patients.Together,our results shed light on the critical role of CBX7 during meningioma malignancy progression and identified the CBX7/USP44/c-MYC/LDHA axis as a promising therapeutic target against meningioma progression.
查看更多>>摘要：Shugoshin-1(Sgo1)is necessary for maintaining sister centromere cohesion and ensuring accurate chromosome segregation during mitosis.It has been reported that the localization of Sgo1 at the centromere is dependent on Bub1-mediated phosphorylation of histone H2A at T120.However,it remains uncertain whether other centromeric proteins play a role in regulating the localization and function of Sgo1 during mitosis.Here,we show that CENP-A interacts with Sgo1 and determines the localization of Sgo1 to the centromere during mitosis.Further biochemical characterization revealed that lysine and arginine residues in the C-terminal domain of Sgo1 are critical for binding CENP-A.Interestingly,the replacement of these basic amino acids with acidic amino acids perturbed the localization of Sgo1 and Aurora B to the centromere,resulting in aberrant chromosome segregation and premature chromatid separation.Taken together,these findings reveal a previously unrecognized but direct link between Sgo1 and CENP-A in centromere plasticity control and illustrate how the Sgo1-CENP-A interaction guides accurate cell division.
查看更多>>摘要：The novel coronavirus pandemic,first reported in December 2019,was caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).SARS-CoV-2 infection leads to a strong immune response and activation of antigen-presenting cells,which can elicit acute respiratory distress syndrome(ARDS)characterized by the rapid onset of widespread inflammation,the so-called cytokine storm.In response to viral infections,monocytes are recruited into the lung and subsequently differentiate into dendritic cells(DCs).DCs are critical players in the development of acute lung inflammation that causes ARDS.Here,we focus on the interaction of a specific SARS-CoV-2 open reading frame protein,ORF8,with DCs.We show that ORF8 binds to DCs,causes pre-maturation of differentiating DCs,and induces the secretion of multiple proinflammatory cytokines by these cells.In addition,we identified DC-SIGN as a possible interaction partner of ORF8 on DCs.Blockade of ORF8 leads to reduced production of IL-1 β,IL-6,IL-12p70,TNF-α,MCP-1(also named CCL2),and IL-10 by DCs.Therefore,a neutralizing antibody blocking the ORF8-mediated cytokine and chemokine response could be an improved therapeutic strategy against SARS-CoV-2.
查看更多>>摘要：Non-alcoholic fatty liver disease(NAFLD),characterized by hepatic steatosis,is one of the commonest causes of liver dysfunction.Adipose triglyceride lipase(ATGL)is closely related to lipid turnover and hepatic steatosis as the speed-limited triacylglycerol lipase in liver lipolysis.However,the expression and regulation of ATGL in NAFLD remain unclear.Herein,our results showed that ATGL protein levels were decreased in the liver tissues of high-fat diet(HFD)-fed mice,naturally obese mice,and cholangioma/hepatic carcinoma patients with hepatic steatosis,as well as in the oleic acid-induced hepatic steatosis cell model,while ATGL mRNA levels were not changed.ATGL protein was mainly degraded through the proteasome pathway in hepatocytes.Beta-transducin repeat containing(BTRC)was upregulated and negatively correlated with the decreased ATGL level in these hepatic steatosis models.Consequently,BTRC was identified as the E3 ligase for ATGL through predominant ubiquitination at the lysine 135 residue.Moreover,adenovirus-mediated knockdown of BTRC ameliorated steatosis in HFD-fed mouse livers and oleic acid-treated liver cells via upregulating the ATGL level.Taken together,BTRC plays a crucial role in hepatic steatosis as a new ATGL E3 ligase and may serve as a potential therapeutic target for treating NAFLD.
查看更多>>摘要：Chronic myeloid leukemia(CML)is a hematopoietic malignancy driven by the fusion gene BCR::ABL1.Drug resistance to tyrosine kinase inhibitors(TKIs)due to BCR::ABL1 mutation and residual leukemia stem cells(LSCs)remain major challenges for CML treatment.Here,we revealed the requirement of vitamin D receptor(VDR)in the progression of CML,in which VDR was upregulated by BCR::ABL1,accounting for its high expression.Interestingly,VDR knockdown inhibited the CML cell proliferation driven by BCR::ABL1,regardless of its mutations with resistance to TKIs.Mechanistically,VDR transcriptionally regulated DDIT4 expression,and the inhibition of DDIT4 triggered DNA damage-induced senescence via p53 signaling activation in CML cells.Furthermore,VDR deficiency was sufficient to not only ameliorate the disease burden and progression in primary CML mice but also reduce the self-renewal of CML-LSCs.Together,our study demonstrated that targeting VDR is a promising strategy to overcome TKI resistance and eradicate LSCs in CML.
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