The paracaspase MALT1 is essential for the activation of NF-κB in response to T cell receptor(TCR)stimula-tion.It recruits downstream TRAF6 and activates the E3 ligase activity of TRAF6 to polyubiquitinate several ta...The paracaspase MALT1 is essential for the activation of NF-κB in response to T cell receptor(TCR)stimula-tion.It recruits downstream TRAF6 and activates the E3 ligase activity of TRAF6 to polyubiquitinate several targets,which ultimately leads to NF-κB activation.Here we identified ubiquitin-specific protease 2a(USP2a)as a MALT1-associated protein by biochemical affinity purification.Endogenous USP2a constitutively interacted with TRAF6,but dynamically interacted with MALT1 and CARMA1 in a stimulation-dependent man-ner.RNA interference(RNAi)-mediated silencing of USP2a attenuated TCR-induced NF-κB activation and production of interleukin-2(IL-2).In addition,the ubiq-uitination of MALT1 and TRAF6 were both suppressed by USP2a knockdown.By knockdown and reconstitu-tion assays,we found that USP2a mediated the interac-tion between MALT1 and TRAF6 in a catalytic activ-ity-dependent manner.Furthermore,USP2a deSUMOy-lated TRAF6.Our findings implicate that USP2a plays an important role in TCR signaling by deSUMOylating TRAF6 and mediating TRAF6-MALT1 interaction.展开更多
目的探讨足月胎盘中去泛素化酶(USP2a)在巨大儿中的调控机制。方法随机选取我院2014年9月~2015年6月分娩的巨大儿29例,另选择同期住院足月分娩正常体重儿31例,采用ELISA技术检测两组产妇胎盘中USP2a蛋白表达;采用Real Time PCR技术检测...目的探讨足月胎盘中去泛素化酶(USP2a)在巨大儿中的调控机制。方法随机选取我院2014年9月~2015年6月分娩的巨大儿29例,另选择同期住院足月分娩正常体重儿31例,采用ELISA技术检测两组产妇胎盘中USP2a蛋白表达;采用Real Time PCR技术检测其下游底物MDM2、CCND1及FASN在两组胎盘中的mRNA表达水平;进一步检测两组孕妇胎盘中MDM2及P53的蛋白表达。结果与对照组相比,巨大儿胎盘中USP2a蛋白含量升高,其下游底物MDM2 mRNA表达水平和蛋白含量高于对照组,P53的蛋白含量低于对照组(P<0.05)。结论胎盘中USP2a的表达水平与巨大儿密切相关。USP2a可能特异性识别靶蛋白MDM2,通过去泛素化作用影响胎盘中MDM2、P53表达水平,进一步影响胎盘的生长发育,从而导致巨大儿的发生。展开更多
MicroRNAs play pivotal roles in the regulation of both innate and adaptive immune responses. In this study, we found that activation of toll-like receptor 4 （TLR4） rapidly increased the level of microRNA-124 （miR- ...MicroRNAs play pivotal roles in the regulation of both innate and adaptive immune responses. In this study, we found that activation of toll-like receptor 4 （TLR4） rapidly increased the level of microRNA-124 （miR- 124） in lipopolysaccharide （LPS）-treated macrophages and mice. MiR-124 knockdown significantly increased the production of the pro-inflammatory cytokine TNF-oL at the post-transcriptional level in LPS-triggered macrophages. Furthermore, miR-124 knockdown or overexpression significanly increased or decreased the protein stability of TNF- α. We found miR-124 directly targeted ubiquitin-specific proteases 2 （USP2） and 14 （USP14）, two components of deubiquitinating enzymes. Knockdown of USP2 and USP14 attenuated the miR-124-mediated protein degradation of TNF-α. Together, our data identify miR-124 as an important feedback negative regulator for LPS-induced pro- duction of TNF-α by targeting USP2 and USP14, thus outlining new mechanisms for fine-tuning the TLR-triggered inflammatory response.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.30700417,30921001 and 31170835)the Ministry of Science and Technology of China(No.2012CB910201).
文摘The paracaspase MALT1 is essential for the activation of NF-κB in response to T cell receptor(TCR)stimula-tion.It recruits downstream TRAF6 and activates the E3 ligase activity of TRAF6 to polyubiquitinate several targets,which ultimately leads to NF-κB activation.Here we identified ubiquitin-specific protease 2a(USP2a)as a MALT1-associated protein by biochemical affinity purification.Endogenous USP2a constitutively interacted with TRAF6,but dynamically interacted with MALT1 and CARMA1 in a stimulation-dependent man-ner.RNA interference(RNAi)-mediated silencing of USP2a attenuated TCR-induced NF-κB activation and production of interleukin-2(IL-2).In addition,the ubiq-uitination of MALT1 and TRAF6 were both suppressed by USP2a knockdown.By knockdown and reconstitu-tion assays,we found that USP2a mediated the interac-tion between MALT1 and TRAF6 in a catalytic activ-ity-dependent manner.Furthermore,USP2a deSUMOy-lated TRAF6.Our findings implicate that USP2a plays an important role in TCR signaling by deSUMOylating TRAF6 and mediating TRAF6-MALT1 interaction.
文摘目的探讨足月胎盘中去泛素化酶(USP2a)在巨大儿中的调控机制。方法随机选取我院2014年9月~2015年6月分娩的巨大儿29例,另选择同期住院足月分娩正常体重儿31例,采用ELISA技术检测两组产妇胎盘中USP2a蛋白表达;采用Real Time PCR技术检测其下游底物MDM2、CCND1及FASN在两组胎盘中的mRNA表达水平;进一步检测两组孕妇胎盘中MDM2及P53的蛋白表达。结果与对照组相比,巨大儿胎盘中USP2a蛋白含量升高,其下游底物MDM2 mRNA表达水平和蛋白含量高于对照组,P53的蛋白含量低于对照组(P<0.05)。结论胎盘中USP2a的表达水平与巨大儿密切相关。USP2a可能特异性识别靶蛋白MDM2,通过去泛素化作用影响胎盘中MDM2、P53表达水平,进一步影响胎盘的生长发育,从而导致巨大儿的发生。
文摘MicroRNAs play pivotal roles in the regulation of both innate and adaptive immune responses. In this study, we found that activation of toll-like receptor 4 （TLR4） rapidly increased the level of microRNA-124 （miR- 124） in lipopolysaccharide （LPS）-treated macrophages and mice. MiR-124 knockdown significantly increased the production of the pro-inflammatory cytokine TNF-oL at the post-transcriptional level in LPS-triggered macrophages. Furthermore, miR-124 knockdown or overexpression significanly increased or decreased the protein stability of TNF- α. We found miR-124 directly targeted ubiquitin-specific proteases 2 （USP2） and 14 （USP14）, two components of deubiquitinating enzymes. Knockdown of USP2 and USP14 attenuated the miR-124-mediated protein degradation of TNF-α. Together, our data identify miR-124 as an important feedback negative regulator for LPS-induced pro- duction of TNF-α by targeting USP2 and USP14, thus outlining new mechanisms for fine-tuning the TLR-triggered inflammatory response.
