NF-κB-inducing kinase （NIK） is required for NF-κB activation based on the processing of NF-κB p100. Here we report a novel mechanism of NIK regulation involving the chaperone 90 kDa heat shock protein （Hsp90） a...NF-κB-inducing kinase （NIK） is required for NF-κB activation based on the processing of NF-κB p100. Here we report a novel mechanism of NIK regulation involving the chaperone 90 kDa heat shock protein （Hsp90） and autophagy. Functional inhibition of lisp90 by the anti-tumor agent geldanamycin （GA） efficiently disrupts its interaction with NIK, resulting in NIK degradation and subsequent blockage of p100 processing. Surprisingly, GA-induced NIK degradation is mediated by autophagy, but largely independent of the ubiquitin-proteasome system. Hsp90 seems to be specifically involved in the folding/stabilization of NIK protein, because GA inhibition does not affect NIK mRNA transcription and translation. Furthermore, Hsp90 is not required for NIK-mediated recruitment of the α subunit of IκB3 kinase to p 100, a key step in induction of p100 processing. These findings define an alternative mechanism for Hsp90 client degradation and identify a novel function ofautophagy in NF-κB regulation. These findings also suggest a new therapeutic strategy for diseases associated with p 100 processing.展开更多
B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing...B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing to LNs has remained unclear.We show here that nuclear factor(NF)-κB-inducing kinase(NIK),a kinase mediating activation of the noncanonical NF-κB pathway,functions in lymphatic endothelial cells(LECs)to regulate B-cell homing to LNs.LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs.The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen.B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells.We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs.Although CCL19 is also expressed in blood endothelial cells(BECs),CXCL13 is not produced in BECs.These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs.展开更多
目的:观察慢病毒介导的NIBP(NIK and IKKβbinding protein)基因转染结肠癌细胞株HT29后,细胞迁移能力以及细胞内p65、MMP2、MMP9 m RNA和蛋白表达的变化。方法:分为未经转染的HT29细胞(HT29组)、转染空载的HT29细胞(HT29-NC组)和转染N...目的:观察慢病毒介导的NIBP(NIK and IKKβbinding protein)基因转染结肠癌细胞株HT29后,细胞迁移能力以及细胞内p65、MMP2、MMP9 m RNA和蛋白表达的变化。方法:分为未经转染的HT29细胞(HT29组)、转染空载的HT29细胞(HT29-NC组)和转染NIBP的HT29细胞(HT29-NIBP稳转组)。采用Transwell试验检测细胞迁移能力;Q-PCR法检测NIBP、p65、MMP2、MMP9的m RNA表达;Western Blot法检测NIBP、p65、磷酸化p65(p-p65)的蛋白表达;ELISA法检测MMP2、MMP9的分泌。结果:高表达NIBP能增强结肠癌细胞株HT29的迁移能力,并主要通过增加p-p65从而促进MMP2、MMP9 m RNA及蛋白表达(P<0.05)。结论:NIBP可能通过激活NF-κB信号通路促进结肠癌细胞分泌MMP-2、MMP-9,从而促进结肠癌细胞的侵袭转移。展开更多
AIM： To find the relationship between hepatitis B virus （HBV） and hepatocytes during the initial state of infection by cDNA microarray. METHODS： Primary normal human hepatocytes （PNHHs） were isolated and infecte...AIM： To find the relationship between hepatitis B virus （HBV） and hepatocytes during the initial state of infection by cDNA microarray. METHODS： Primary normal human hepatocytes （PNHHs） were isolated and infected with HBV. From the PNHHs, RNA was isolated and inverted into complement DNA （cDNA） with Cy3- or Cy5- labeled dUTP for microarray analysis. The labeled cDNA was hybridized with microarray chip, including 4224 cDNAs. From the image of the microarray, expression profiles were produced and some of them were confirmed by RT-PCR, immunoblot analysis, and NF-κB luciferase reporter assay. RESULTS： From the cDNA microarray, we obtained 98 differentially regulated genes. Of the 98 genes, 53 were up regulated and 45 down regulated. Interestingly, in the up regulated genes, we found the TNF signaling pathway-related genes： LT-α, TRAF2, and NIK. By using RT-PCR, we confirmed the up-regulation of these genes in HepG2, HuhT, and Chang liver cells, which were transfected with pHBV1.2x, a plasmid encoding all HBV messages. Moreover, these three genes participated in HBV- mediated NF-κB activation. CONCLUSION： During the initial state of HBV infection, hepatocytes facilitate the activation of NF-κB through up regulation of LT-α, TRAF2, and NIK.展开更多
Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling a...Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.展开更多
飞人专卖店亮相申城中国特色产品成为焦点关键词:JORDAN专卖店中国特色庆典随着上海港汇广场Jordan专卖店的开幕,第一双Jordan品牌专门为中国所设计的Air Jordan 1 XQ (飞人乔丹一代庆典版)揭开神秘面纱,出现在媒体面前。据悉,这个特别...飞人专卖店亮相申城中国特色产品成为焦点关键词:JORDAN专卖店中国特色庆典随着上海港汇广场Jordan专卖店的开幕,第一双Jordan品牌专门为中国所设计的Air Jordan 1 XQ (飞人乔丹一代庆典版)揭开神秘面纱,出现在媒体面前。据悉,这个特别款的球鞋将于6月1号只在中国正式发售——全球限量仅240双。展开更多
文摘NF-κB-inducing kinase （NIK） is required for NF-κB activation based on the processing of NF-κB p100. Here we report a novel mechanism of NIK regulation involving the chaperone 90 kDa heat shock protein （Hsp90） and autophagy. Functional inhibition of lisp90 by the anti-tumor agent geldanamycin （GA） efficiently disrupts its interaction with NIK, resulting in NIK degradation and subsequent blockage of p100 processing. Surprisingly, GA-induced NIK degradation is mediated by autophagy, but largely independent of the ubiquitin-proteasome system. Hsp90 seems to be specifically involved in the folding/stabilization of NIK protein, because GA inhibition does not affect NIK mRNA transcription and translation. Furthermore, Hsp90 is not required for NIK-mediated recruitment of the α subunit of IκB3 kinase to p 100, a key step in induction of p100 processing. These findings define an alternative mechanism for Hsp90 client degradation and identify a novel function ofautophagy in NF-κB regulation. These findings also suggest a new therapeutic strategy for diseases associated with p 100 processing.
基金by grants from the National Institutes of Health(GM84459,AI057555,AI104519 and AI64639)This study also used the NIH/NCI-supported resources under award number P30CA016672 at The MD Anderson Cancer CenterSZ was supported by a scholarship from the China Scholarship Council(CSC)under the Grant CSC 201506210393.
文摘B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing to LNs has remained unclear.We show here that nuclear factor(NF)-κB-inducing kinase(NIK),a kinase mediating activation of the noncanonical NF-κB pathway,functions in lymphatic endothelial cells(LECs)to regulate B-cell homing to LNs.LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs.The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen.B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells.We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs.Although CCL19 is also expressed in blood endothelial cells(BECs),CXCL13 is not produced in BECs.These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs.
基金supported by the Natural Science Foundation of Gansu Province,China(No.20JR5RA369)Health Industry Re‐search Plan Project of Gansu Province,China(No.GSWSKY 2021-009)Lanzhou University Medical Research Innovation Abil‐ity Improvement Project(No.lzuyxcx-2022-187).
文摘骨骼肌质量维持的分子机制涉及多种信号通路之间的相互作用。在正常生理条件下,相互交叉的信号通路用于控制和协调骨骼肌肥大和萎缩,最终使肌肉蛋白质合成和降解之间达到平衡。当蛋白质合成的总速率超过蛋白质降解的速率时,肌肉逐渐肥大,而当蛋白质合成的总速率低于蛋白质降解的速率时,肌肉则发生萎缩。肌细胞萎缩中主要涉及两种蛋白质降解途径,即泛素(ubiquitin,Ub)-蛋白酶体途径和自噬-溶酶体途径(autophagy-lysosomal pathway,ALP)。蛋白质降解途径在肌肉萎缩期间被激活,导致肌肉质量的损失。肌肉萎缩可在营养不良、衰老以及恶病质等多种条件下出现,骨科疾病引发的骨骼肌萎缩主要包括骨折导致的失用性肌萎缩以及去神经性肌萎缩。控制和协调骨骼肌蛋白质合成及降解的信号通路包括胰岛素样生长因子1(insulin-like growth factor 1,IGF1)-Akt-哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)、肌生长抑制素(myostatin)-激活素A(activin A)-Smad、G蛋白α抑制活性多肽2(G proteinαinhibitory peptide 2,Gαi2)-PKC、核因子κB(nuclear factorκB,NF-κB)、外胚层发育不良A2受体(ectodysplasin A2 receptor,EDA2R)-NF-κB诱导激酶(NF-κB inducing kinase,NIK)、丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路。本文综述了骨骼肌发生萎缩时蛋白质的降解途径及调节肌萎缩蛋白质降解的相关信号通路。
文摘目的:观察慢病毒介导的NIBP(NIK and IKKβbinding protein)基因转染结肠癌细胞株HT29后,细胞迁移能力以及细胞内p65、MMP2、MMP9 m RNA和蛋白表达的变化。方法:分为未经转染的HT29细胞(HT29组)、转染空载的HT29细胞(HT29-NC组)和转染NIBP的HT29细胞(HT29-NIBP稳转组)。采用Transwell试验检测细胞迁移能力;Q-PCR法检测NIBP、p65、MMP2、MMP9的m RNA表达;Western Blot法检测NIBP、p65、磷酸化p65(p-p65)的蛋白表达;ELISA法检测MMP2、MMP9的分泌。结果:高表达NIBP能增强结肠癌细胞株HT29的迁移能力,并主要通过增加p-p65从而促进MMP2、MMP9 m RNA及蛋白表达(P<0.05)。结论:NIBP可能通过激活NF-κB信号通路促进结肠癌细胞分泌MMP-2、MMP-9,从而促进结肠癌细胞的侵袭转移。
基金Supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea, No. A050145
文摘AIM： To find the relationship between hepatitis B virus （HBV） and hepatocytes during the initial state of infection by cDNA microarray. METHODS： Primary normal human hepatocytes （PNHHs） were isolated and infected with HBV. From the PNHHs, RNA was isolated and inverted into complement DNA （cDNA） with Cy3- or Cy5- labeled dUTP for microarray analysis. The labeled cDNA was hybridized with microarray chip, including 4224 cDNAs. From the image of the microarray, expression profiles were produced and some of them were confirmed by RT-PCR, immunoblot analysis, and NF-κB luciferase reporter assay. RESULTS： From the cDNA microarray, we obtained 98 differentially regulated genes. Of the 98 genes, 53 were up regulated and 45 down regulated. Interestingly, in the up regulated genes, we found the TNF signaling pathway-related genes： LT-α, TRAF2, and NIK. By using RT-PCR, we confirmed the up-regulation of these genes in HepG2, HuhT, and Chang liver cells, which were transfected with pHBV1.2x, a plasmid encoding all HBV messages. Moreover, these three genes participated in HBV- mediated NF-κB activation. CONCLUSION： During the initial state of HBV infection, hepatocytes facilitate the activation of NF-κB through up regulation of LT-α, TRAF2, and NIK.
基金This study was supported by grants from the National Institutes of Health(AI64639 and GM84459)the core facilities of MD Anderson Cancer Center are supported by the NIH/NCI Cancer Center Support Grant(CCSG)P30CA016672.
文摘Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.
文摘飞人专卖店亮相申城中国特色产品成为焦点关键词:JORDAN专卖店中国特色庆典随着上海港汇广场Jordan专卖店的开幕,第一双Jordan品牌专门为中国所设计的Air Jordan 1 XQ (飞人乔丹一代庆典版)揭开神秘面纱,出现在媒体面前。据悉,这个特别款的球鞋将于6月1号只在中国正式发售——全球限量仅240双。
