MAP kinases are evolutionarily conserved signaling regulators from budding yeast to mammals and play essential roles in both innate and adaptive immune responses.There are three main families of MAPKs in mammals.Each ...MAP kinases are evolutionarily conserved signaling regulators from budding yeast to mammals and play essential roles in both innate and adaptive immune responses.There are three main families of MAPKs in mammals.Each of them has its own activators,inactivators,substrates and scaffolds,which altogether form a fine signaling network in response to different extracellular or intracellular stimulation.In this review,we summarize recent advances in understanding of the regulation of MAP kinases and the roles of MAP kinases in innate and adaptive immune responses.Cellular & Molecular Immunology.2005;2(1):20-27.展开更多
As a newly discovered type of RNA, circular RNAs(circRNAs) are widespread throughout the eukaryotic genome. The expression of circRNAs is regulated by both cis-elements and trans-factors, and the expression pattern of...As a newly discovered type of RNA, circular RNAs(circRNAs) are widespread throughout the eukaryotic genome. The expression of circRNAs is regulated by both cis-elements and trans-factors, and the expression pattern of circRNAs is cell type-and diseasespecific. Similar to other types of non-coding RNAs, functions of circRNAs are also versatile. CircRNAs have been reported previously to function as microRNA(miRNA) sponges, protein sponges, coding RNAs or scaffolds for protein complexes.Recently, several circRNAs have been reported to play important roles in human malignancies, including glioma. Here, we reviewed several reports related to circRNAs and glioma, as well as the potential diagnostic and therapeutic applications of circRNAs in brain cancer. In general, some circRNAs, such as circSMARCA5 and circCFH, are found to be expressed in a gliomaspecific pattern, these circRNAs may be used as tumor biomarkers. In addition, some circRNAs have been found to play oncogenic roles in glioma(e.g., circNFIX and circNT5E), whereas others have been reported to function as tumor suppressors(e.g.,circFBXW7 and circSHPRH). Furthermore, circRNA is a good tool for protein expression because of its higher stability compared to linear RNAs. Thus, circRNAs may also be an ideal choice for gene/protein delivery in future brain cancer therapies. There are some challenges in circRNA research in glioma and other diseases. Research related to circRNAs in glioma is comparatively new and many mysteries remain to be solved.展开更多
Mitogen-activated protein kinase(MAPK)cascades regulate a myriad of plant biological processes,including disease resistance.Plant genomes encode a large number of MAPK kinase kinases(MAPKKKs)that can be divided into t...Mitogen-activated protein kinase(MAPK)cascades regulate a myriad of plant biological processes,including disease resistance.Plant genomes encode a large number of MAPK kinase kinases(MAPKKKs)that can be divided into two subfamilies,namely MEKK-like kinases and Raf-like kinases.Thus far,the func-tions of MEKK-like MAPKKKs have been relatively well characterized,but the roles of Raf-like MAPKKKs in.plant MAPK cascades remain less understood.Here,we report the role of OsEDR1,a Raf-like MAPKKK,in the regulation of the MAPK cascade in rice response tp the bacterial pathogen Xanthomonas oryzae pv.oryzicola(Xoc).We found that OsEDR1 inhibits OsMPKK10.2(a MAPK kinase)activity through physical interaction.Upon Xoc infection,OsMPKK10.2 is phosphorylated at S304 to activate OsMPK6(a MAPK).Interestingly,activated OsMPK6 phosphorylates OsEDR1 at S861,which destabilizes OsEDR1 and thus releases the inhibition of OsMPKK10.2,leading to increased OsMPKK10.2 activity and enhanced resistance of rice plants to Xoc.Taken together,these results provide new insights into the functions of Raf-like ki-nases in the regulation of the MAPK cascade in plant immunity.展开更多
Grain formation is fundamental for crop yield but is vulnerable to abiotic and biotic stresses.Rice grain production is threatened by the false smut fungus Ustilaginoidea virens,which specifically infects rice floral ...Grain formation is fundamental for crop yield but is vulnerable to abiotic and biotic stresses.Rice grain production is threatened by the false smut fungus Ustilaginoidea virens,which specifically infects rice floral organs,disrupting fertilization and seed formation.However,little is known about the molecular mechanisms of the U.virens-rice interaction and the genetic basis of floral resistance.Here,we report that U.virens secretes a cytoplasmic effector,UvCBP1,to facilitate infection of rice flowers.Mechanistically,UvCBP1 interacts with the rice scaffold protein OsRACK1A and competes its interaction with the reduced nicotinamide adenine dinucleotide phosphate oxidase OsRBOHB,leading to inhibition of reactive oxygen species(ROS)production.Although the analysis of natural variation revealed no OsRACK1A variants that could avoid being targeted by UvCBP1,expression levels of OsRACK1A are correlated with field resistance against U.virens in rice germplasm.Overproduction of OsRACK1A restores the OsRACK1A-OsRBOHB association and promotes OsRBOHB phosphorylation to enhance ROS production,conferring rice floral resistance to U.virens without yield penalty.Taken together,our findings reveal a new pathogenic mechanism mediated by an essential effector from a flower-specific pathogen and provide a valuable genetic resource for balancing disease resistance and crop yield.展开更多
PIAS(protein inhibitor of activated STAT)蛋白家族能够与许多蛋白质发生相互作用,其中大部分为转录因子。通过相互作用,PIAS蛋白通过影响了蛋白的活性和功能,参与基因的转录调控和包括STAT(Signal transducer and activator of trans...PIAS(protein inhibitor of activated STAT)蛋白家族能够与许多蛋白质发生相互作用,其中大部分为转录因子。通过相互作用,PIAS蛋白通过影响了蛋白的活性和功能,参与基因的转录调控和包括STAT(Signal transducer and activator of transcription),Wnt,TGFβ,NF-κB等通路在内的细胞信号通路,具有重要的生理功能。PIAS蛋白的调控机制主要有两种:一种是通过其自身所具有的SUMO(small ubiquitin-related modifiers)E3连接酶活性,促进对一些转录因子、转录辅因子的化学修饰,尤其是SUMO化修饰,从而调控它们的转录活性;另一种是作为构架蛋白,为蛋白质之间的相互作用提供平台,促进细胞信号通路复合物或基因转录复合物中其它调节蛋白的去除和募集,并涉及到靶蛋白的亚核定位。同时,针对不同的靶蛋白,PIAS蛋白的上述两种作用机制并不是完全互相排斥的,这体现了PIAS蛋白功能的特异性和复杂性。本篇综述将就上述内容作一介绍。展开更多
Deubiquitinating enzymes(DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin-proteasome degradation and are critical for regulating protein expression levels in vivo.Therefore,dissecting...Deubiquitinating enzymes(DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin-proteasome degradation and are critical for regulating protein expression levels in vivo.Therefore,dissecting the underlying mechanism of DUB recognition is needed to advance the development of drugs related to DUB signaling pathways.To data,extensive studies on the ubiquitin chain specificity of DUBs have been reported,but substrate protein recognition is still not clearly understood.As a breakthrough,the scaffolding role may be significant to substrate protein selectivity.From this perspective,we systematically characterized the scaffolding proteins and complexes contributing to DUB substrate selectivity.Furthermore,we proposed a deubiquitination complex platform(DCP) as a potentially generic mechanism for DUB substrate recognition based on known examples,which might fill the gaps in the understanding of DUB substrate specificity.展开更多
Plants have adopted versatile scaffold proteins to facilitate the crosstalk between multiple signaling pathways. Leaf senescence is a well-programmed developmental stage that is coordinated by various external and int...Plants have adopted versatile scaffold proteins to facilitate the crosstalk between multiple signaling pathways. Leaf senescence is a well-programmed developmental stage that is coordinated by various external and internal signals. However,the functions of plant scaffold proteins in response to senescence signals are not well understood. Here, we report that the scaffold protein RACK1A(RECEPTOR FOR ACTIVATED C KINASE1A) participates in leaf senescence mediated by ethylene signaling via the coordination of the EIN3-miR164-ORE1 transcriptional regulatory cascade. RACK1A is a novel positive regulator of ethylene-mediated leaf senescence. The rack1a mutant exhibits delayed leaf senescence, while transgenic lines overexpressing RACK1A display early leaf senescence. Moreover, RACK1A promotes EIN3(ETHYLENE INSENSITIVE 3) protein accumulation, and directly interacts with EIN3 to enhance its DNA-binding activity. Together, they then associate with the miR164 promoter to inhibit its transcription, leading to the release of the inhibition on downstream ORE1(ORESARA 1) transcription and the promotion of leaf senescence.This study reveals a mechanistic framework by which RACK1A promotes leaf senescence via the EIN3-miR164-ORE1 transcriptional cascade, and provides a paradigm for how scaffold proteins finely tune phytohormone signaling to control plant development.展开更多
Asymmetric cell division is an important mechanism for creating diversity in a cellular population. Stem cells commonly perform asymmetric division to generate both a daughter stem cell for self-renewal and a more dif...Asymmetric cell division is an important mechanism for creating diversity in a cellular population. Stem cells commonly perform asymmetric division to generate both a daughter stem cell for self-renewal and a more differentiated daughter cell to populate the tissue. During asymmetric cell division, protein cell fate determinants asymmetrically localize to the opposite poles of a dividing cell to cause distinct cell fate. However, it remains unclear whether cell fate determination is robust to fluctuations and noise during this spatial allocation process. To answer this question, we engineered Caulobacter, a bacterial model for asymmetric division, to express synthetic scaffolds with modular protein interaction domains. These scaffolds perturbed the spatial distribution of the PleC-DivJ- DivK phospho-signaling network without changing their endogenous expression levels. Surprisingly, enforcing symmetrical distribution of these cell fate de terminants did not result in symmetric daughter fate or any morphological defects. Further computational analysis suggested that PleC and DivJ form a robust phospho-switch that can tolerate high amount of spatial variation. This insight may shed light on the presence of similar phospho-switches in stem cell asymmetric division regulation. Overall, our study demonstrates that synthetic protein scaffolds can provide a useful tool to probe biological systems for better understanding of their operating principles.展开更多
文摘MAP kinases are evolutionarily conserved signaling regulators from budding yeast to mammals and play essential roles in both innate and adaptive immune responses.There are three main families of MAPKs in mammals.Each of them has its own activators,inactivators,substrates and scaffolds,which altogether form a fine signaling network in response to different extracellular or intracellular stimulation.In this review,we summarize recent advances in understanding of the regulation of MAP kinases and the roles of MAP kinases in innate and adaptive immune responses.Cellular & Molecular Immunology.2005;2(1):20-27.
文摘As a newly discovered type of RNA, circular RNAs(circRNAs) are widespread throughout the eukaryotic genome. The expression of circRNAs is regulated by both cis-elements and trans-factors, and the expression pattern of circRNAs is cell type-and diseasespecific. Similar to other types of non-coding RNAs, functions of circRNAs are also versatile. CircRNAs have been reported previously to function as microRNA(miRNA) sponges, protein sponges, coding RNAs or scaffolds for protein complexes.Recently, several circRNAs have been reported to play important roles in human malignancies, including glioma. Here, we reviewed several reports related to circRNAs and glioma, as well as the potential diagnostic and therapeutic applications of circRNAs in brain cancer. In general, some circRNAs, such as circSMARCA5 and circCFH, are found to be expressed in a gliomaspecific pattern, these circRNAs may be used as tumor biomarkers. In addition, some circRNAs have been found to play oncogenic roles in glioma(e.g., circNFIX and circNT5E), whereas others have been reported to function as tumor suppressors(e.g.,circFBXW7 and circSHPRH). Furthermore, circRNA is a good tool for protein expression because of its higher stability compared to linear RNAs. Thus, circRNAs may also be an ideal choice for gene/protein delivery in future brain cancer therapies. There are some challenges in circRNA research in glioma and other diseases. Research related to circRNAs in glioma is comparatively new and many mysteries remain to be solved.
基金This work was supported by grants from the National Natural Science Foundation of China(31772145 and 31901865)Huazhong Agricultural University Scientific&Technological Self-innovation Foundation(2012YB02).
文摘Mitogen-activated protein kinase(MAPK)cascades regulate a myriad of plant biological processes,including disease resistance.Plant genomes encode a large number of MAPK kinase kinases(MAPKKKs)that can be divided into two subfamilies,namely MEKK-like kinases and Raf-like kinases.Thus far,the func-tions of MEKK-like MAPKKKs have been relatively well characterized,but the roles of Raf-like MAPKKKs in.plant MAPK cascades remain less understood.Here,we report the role of OsEDR1,a Raf-like MAPKKK,in the regulation of the MAPK cascade in rice response tp the bacterial pathogen Xanthomonas oryzae pv.oryzicola(Xoc).We found that OsEDR1 inhibits OsMPKK10.2(a MAPK kinase)activity through physical interaction.Upon Xoc infection,OsMPKK10.2 is phosphorylated at S304 to activate OsMPK6(a MAPK).Interestingly,activated OsMPK6 phosphorylates OsEDR1 at S861,which destabilizes OsEDR1 and thus releases the inhibition of OsMPKK10.2,leading to increased OsMPKK10.2 activity and enhanced resistance of rice plants to Xoc.Taken together,these results provide new insights into the functions of Raf-like ki-nases in the regulation of the MAPK cascade in plant immunity.
基金National Natural Science Foundation of China,China(32072503 to J.F.,U19A2033 to W.-M.W.,and 32121003 to X.C.)Sichuan Youth Science and Technology Innovation Research Team(2022JDTD0023 to J.F.)Sichuan Applied Fundamental Research Foundation(2020JDJQ0040 to J.W.).
文摘Grain formation is fundamental for crop yield but is vulnerable to abiotic and biotic stresses.Rice grain production is threatened by the false smut fungus Ustilaginoidea virens,which specifically infects rice floral organs,disrupting fertilization and seed formation.However,little is known about the molecular mechanisms of the U.virens-rice interaction and the genetic basis of floral resistance.Here,we report that U.virens secretes a cytoplasmic effector,UvCBP1,to facilitate infection of rice flowers.Mechanistically,UvCBP1 interacts with the rice scaffold protein OsRACK1A and competes its interaction with the reduced nicotinamide adenine dinucleotide phosphate oxidase OsRBOHB,leading to inhibition of reactive oxygen species(ROS)production.Although the analysis of natural variation revealed no OsRACK1A variants that could avoid being targeted by UvCBP1,expression levels of OsRACK1A are correlated with field resistance against U.virens in rice germplasm.Overproduction of OsRACK1A restores the OsRACK1A-OsRBOHB association and promotes OsRBOHB phosphorylation to enhance ROS production,conferring rice floral resistance to U.virens without yield penalty.Taken together,our findings reveal a new pathogenic mechanism mediated by an essential effector from a flower-specific pathogen and provide a valuable genetic resource for balancing disease resistance and crop yield.
文摘PIAS(protein inhibitor of activated STAT)蛋白家族能够与许多蛋白质发生相互作用,其中大部分为转录因子。通过相互作用,PIAS蛋白通过影响了蛋白的活性和功能,参与基因的转录调控和包括STAT(Signal transducer and activator of transcription),Wnt,TGFβ,NF-κB等通路在内的细胞信号通路,具有重要的生理功能。PIAS蛋白的调控机制主要有两种:一种是通过其自身所具有的SUMO(small ubiquitin-related modifiers)E3连接酶活性,促进对一些转录因子、转录辅因子的化学修饰,尤其是SUMO化修饰,从而调控它们的转录活性;另一种是作为构架蛋白,为蛋白质之间的相互作用提供平台,促进细胞信号通路复合物或基因转录复合物中其它调节蛋白的去除和募集,并涉及到靶蛋白的亚核定位。同时,针对不同的靶蛋白,PIAS蛋白的上述两种作用机制并不是完全互相排斥的,这体现了PIAS蛋白功能的特异性和复杂性。本篇综述将就上述内容作一介绍。
基金supported by National Natural Science Foundation of China(No.U21A20420 to Bo Yang)Zhejiang Provincial Natural Science Foundation(No.LR22H310002 to Ji Cao,China)。
文摘Deubiquitinating enzymes(DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin-proteasome degradation and are critical for regulating protein expression levels in vivo.Therefore,dissecting the underlying mechanism of DUB recognition is needed to advance the development of drugs related to DUB signaling pathways.To data,extensive studies on the ubiquitin chain specificity of DUBs have been reported,but substrate protein recognition is still not clearly understood.As a breakthrough,the scaffolding role may be significant to substrate protein selectivity.From this perspective,we systematically characterized the scaffolding proteins and complexes contributing to DUB substrate selectivity.Furthermore,we proposed a deubiquitination complex platform(DCP) as a potentially generic mechanism for DUB substrate recognition based on known examples,which might fill the gaps in the understanding of DUB substrate specificity.
基金supported by grants from the National Natural Science Foundation of China (32070292 to J.L.)Shenzhen Science and Technology Program (KQTD2019 0929173906742 to J.L.)+1 种基金The Key Laboratory of Molecular Design for Plant Cell Factory of Guangdong Higher Education Institutes (2019KSYS006 to J.L.)Scientific Research Funding for postdoctoral researchers staying at Shenzhen (K19227561, K21227504 to W.Z.)。
文摘Plants have adopted versatile scaffold proteins to facilitate the crosstalk between multiple signaling pathways. Leaf senescence is a well-programmed developmental stage that is coordinated by various external and internal signals. However,the functions of plant scaffold proteins in response to senescence signals are not well understood. Here, we report that the scaffold protein RACK1A(RECEPTOR FOR ACTIVATED C KINASE1A) participates in leaf senescence mediated by ethylene signaling via the coordination of the EIN3-miR164-ORE1 transcriptional regulatory cascade. RACK1A is a novel positive regulator of ethylene-mediated leaf senescence. The rack1a mutant exhibits delayed leaf senescence, while transgenic lines overexpressing RACK1A display early leaf senescence. Moreover, RACK1A promotes EIN3(ETHYLENE INSENSITIVE 3) protein accumulation, and directly interacts with EIN3 to enhance its DNA-binding activity. Together, they then associate with the miR164 promoter to inhibit its transcription, leading to the release of the inhibition on downstream ORE1(ORESARA 1) transcription and the promotion of leaf senescence.This study reveals a mechanistic framework by which RACK1A promotes leaf senescence via the EIN3-miR164-ORE1 transcriptional cascade, and provides a paradigm for how scaffold proteins finely tune phytohormone signaling to control plant development.
文摘Asymmetric cell division is an important mechanism for creating diversity in a cellular population. Stem cells commonly perform asymmetric division to generate both a daughter stem cell for self-renewal and a more differentiated daughter cell to populate the tissue. During asymmetric cell division, protein cell fate determinants asymmetrically localize to the opposite poles of a dividing cell to cause distinct cell fate. However, it remains unclear whether cell fate determination is robust to fluctuations and noise during this spatial allocation process. To answer this question, we engineered Caulobacter, a bacterial model for asymmetric division, to express synthetic scaffolds with modular protein interaction domains. These scaffolds perturbed the spatial distribution of the PleC-DivJ- DivK phospho-signaling network without changing their endogenous expression levels. Surprisingly, enforcing symmetrical distribution of these cell fate de terminants did not result in symmetric daughter fate or any morphological defects. Further computational analysis suggested that PleC and DivJ form a robust phospho-switch that can tolerate high amount of spatial variation. This insight may shed light on the presence of similar phospho-switches in stem cell asymmetric division regulation. Overall, our study demonstrates that synthetic protein scaffolds can provide a useful tool to probe biological systems for better understanding of their operating principles.
