Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as ...Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.展开更多
Transforming growth factor β （TGFβ） controls cellular behavior in embryonic and adult tissues. TGFβ binding to serine/threonine kinase receptors on the plasma membrane activates Smad molecules and additional sign...Transforming growth factor β （TGFβ） controls cellular behavior in embryonic and adult tissues. TGFβ binding to serine/threonine kinase receptors on the plasma membrane activates Smad molecules and additional signaling proteins that together regulate gene expression. In this review, mechanisms and models that aim at explaining the coordination between several components of the signaling network downstream of TGFβ are presented. We discuss how the activity and duration of TGFβ receptor/Smad signaling can be regulated by post-translational modifications that affect the stability of key proteins in the pathway. We highlight finks between these mechanisms and human diseases, such as tissue fibrosis and cancer.展开更多
Transforming growth factor-β （TGF-β） members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II （TβR II） and type I （TβRI） and serine/threonine kinases recep...Transforming growth factor-β （TGF-β） members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II （TβR II） and type I （TβRI） and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes （DUBs）. In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regula- tory roles of these DUBs as a driving force for cancer progression as well as their underlying working mech- anisms are also discussed.展开更多
Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serv...Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serving to ensure cell homeostasis and guarantee life activities.The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels(phosphorylation,acetylation,methylation,etc.)but also at the protein level(activators or repressors).When regulatory mechanisms are aberrant,the altered biological processes may subsequently induce serious human diseases,especially various types of cancer.In tumorigenesis,the altered biological processes involve tumor metabolism,the immunological tumor microenvironment(TME),cancer stem cell(CSC)stemness and so on.With regard to tumor metabolism,the ubiquitination of some key proteins such as RagA,mTOR,PTEN,AKT,c-Myc and P53 significantly regulates the activity of the mTORC1,AMPK and PTEN-AKT signaling pathways.In addition,ubiquitination in the TLR,RLR and STING-dependent signaling pathways also modulates the TME.Moreover,the ubiquitination of core stem cell regulator triplets(Nanog,Oct4 and Sox2)and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness.Based on the altered components,including the proteasome,E3 ligases,E1,E2 and deubiquitinases(DUBs),many molecular targeted drugs have been developed to combat cancer.Among them,small molecule inhibitors targeting the proteasome,such as bortezomib,carfilzomib,oprozomib and ixazomib,have achieved tangible success.In addition,MLN7243 and MLN4924(targeting the E1 enzyme),Leucettamol A and CC0651(targeting the E2 enzyme),nutlin and MI‐219(targeting the E3 enzyme),and compounds G5 and F6(targeting DUB activity)have also shown potential in preclinical cancer treatment.In this review,we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation,TME mo展开更多
The NF-κB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-KB is achieved by K63-1inked polyubiquitination of key signaling molecules which recruit kin...The NF-κB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-KB is achieved by K63-1inked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the IKB kinase （IKK）. Ubiquitination is a highly dynamic process and is balanced by deubiquitinases that cleave polyubiquitin chains and terminate downstream signaling events. The A20 deubiquitinase is a critical negative regulator of NF-κB and inflammation, since A20-deficient mice develop uncontrolled and spontaneous multi-organ inflammation. Furthermore, specific polymorphisms in the A20 genomic locus predispose humans to autoimmune disease. Recent studies also indicate that A20 is an important tumor suppressor that is inactivated in B-cell lymphomas. Therefore, targeting A20 may form the basis of novel therapies for autoimmune disease and lymphomas.展开更多
Green plants on the earth have evolved intricate mechanisms to acclimatize to and utilize sunlight.In Arabidopsis,light signals are perceived by photoreceptors and transmitted through divergent but overlapping signali...Green plants on the earth have evolved intricate mechanisms to acclimatize to and utilize sunlight.In Arabidopsis,light signals are perceived by photoreceptors and transmitted through divergent but overlapping signaling networks to modulate plant photomorphogenic development.COP1(CONSTITUTIVE PHOTOMORPHOGENIC 1)was first cloned as a central repressor of photomorphogenesis in higher plants and has been extensively studied for over 30 years.It acts as a RING E3 ubiquitin ligase downstream of multiple photoreceptors to target key light-signaling regulators for degradation,primarily as part of large protein complexes.The mammalian counterpart of COP1 is a pluripotent regulator of tumorigenesis and metabolism.A great deal of information on COP1 has been derived from whole-genome sequencing and functional studies in lower green plants,which enables us to illustrate its evolutionary history.Here,we reviewthe current understanding about COP1,with a focus on the conservation and functional diversification of COP1 and its signaling partners in different taxonomic clades.展开更多
Since its discovery in the late 1970s, the ubiquitin proteasome pathway appears to be omnipresent in many research fields. Although originally discovered in animals, the pathway has a very central role in plants, whic...Since its discovery in the late 1970s, the ubiquitin proteasome pathway appears to be omnipresent in many research fields. Although originally discovered in animals, the pathway has a very central role in plants, which may be correlated to their sessile lifestyle. E3 ligases function as flexible and highly diverse key regulators within the path- way by targeting substrate proteins for ubiquitylation, and often proteolytic degradation via the 26S proteasome. This review provides a concise overview on the most common classes of E3 ligases so far described in plants, and emphasizes recent findings regarding these interesting and flexible enzymes and their diverse functions in plant biology.展开更多
Recent discovery of PYR/PYL/RCAR-type abscisic acid （ABA） receptors has become one of most significant advances in plant science in the past decade. In mammals, endosomal sorting acts as an important pathway to down...Recent discovery of PYR/PYL/RCAR-type abscisic acid （ABA） receptors has become one of most significant advances in plant science in the past decade. In mammals, endosomal sorting acts as an important pathway to downregulate different types of receptors, but its role in plant hormone signaling is poorly understood. Here, we report that an ubiquitin E2-1ike protein, VPS23A, which is a key component of ESCRT-I, negatively regulates ABA signaling. VPS23A has epistatic relationship with PYR/PYL/RCAR-type ABA receptors and disruption of VPS23A enhanced the activity of key kinase OST1 in the ABA signaling pathway under ABA treatment. Moreover, VPS23A interacts with PYR1/PYLs and K63-1inked diubiquitin, and PYL4 possesses K63-1inked ubiquitinated modification in vivo. Further analysis revealed that VPS23A affects the subcellular localization of PYR 1 and the stability of PYL4. Taken together, our results suggest that VPS23A affects PYR1/ PYL4 via vacuole-mediated degradation, providing an advanced understanding of both the turnover of ABA receptors and ESCRTs in plant hormone signaling.展开更多
文摘Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.
文摘Transforming growth factor β （TGFβ） controls cellular behavior in embryonic and adult tissues. TGFβ binding to serine/threonine kinase receptors on the plasma membrane activates Smad molecules and additional signaling proteins that together regulate gene expression. In this review, mechanisms and models that aim at explaining the coordination between several components of the signaling network downstream of TGFβ are presented. We discuss how the activity and duration of TGFβ receptor/Smad signaling can be regulated by post-translational modifications that affect the stability of key proteins in the pathway. We highlight finks between these mechanisms and human diseases, such as tissue fibrosis and cancer.
文摘Transforming growth factor-β （TGF-β） members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II （TβR II） and type I （TβRI） and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes （DUBs）. In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regula- tory roles of these DUBs as a driving force for cancer progression as well as their underlying working mech- anisms are also discussed.
基金supported by grants from the National Natural Science Foundation of China(Nos.31801177,81702659,31830053,31920103007,81625019)the Science Technology Commission of Shanghai Municipality(No.18410722000)+1 种基金the Shanghai Sailing Program(No.18YF1419500)the Fundamental Research Funds for the Central Universities(No.22120180043).
文摘Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serving to ensure cell homeostasis and guarantee life activities.The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels(phosphorylation,acetylation,methylation,etc.)but also at the protein level(activators or repressors).When regulatory mechanisms are aberrant,the altered biological processes may subsequently induce serious human diseases,especially various types of cancer.In tumorigenesis,the altered biological processes involve tumor metabolism,the immunological tumor microenvironment(TME),cancer stem cell(CSC)stemness and so on.With regard to tumor metabolism,the ubiquitination of some key proteins such as RagA,mTOR,PTEN,AKT,c-Myc and P53 significantly regulates the activity of the mTORC1,AMPK and PTEN-AKT signaling pathways.In addition,ubiquitination in the TLR,RLR and STING-dependent signaling pathways also modulates the TME.Moreover,the ubiquitination of core stem cell regulator triplets(Nanog,Oct4 and Sox2)and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness.Based on the altered components,including the proteasome,E3 ligases,E1,E2 and deubiquitinases(DUBs),many molecular targeted drugs have been developed to combat cancer.Among them,small molecule inhibitors targeting the proteasome,such as bortezomib,carfilzomib,oprozomib and ixazomib,have achieved tangible success.In addition,MLN7243 and MLN4924(targeting the E1 enzyme),Leucettamol A and CC0651(targeting the E2 enzyme),nutlin and MI‐219(targeting the E3 enzyme),and compounds G5 and F6(targeting DUB activity)have also shown potential in preclinical cancer treatment.In this review,we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation,TME mo
基金supported by the National Natural Science Foundation of China(No.30771140)the Scientific Research Project of Educational Department of Henan ProvinceChina(No.13A310070)
文摘The NF-κB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-KB is achieved by K63-1inked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the IKB kinase （IKK）. Ubiquitination is a highly dynamic process and is balanced by deubiquitinases that cleave polyubiquitin chains and terminate downstream signaling events. The A20 deubiquitinase is a critical negative regulator of NF-κB and inflammation, since A20-deficient mice develop uncontrolled and spontaneous multi-organ inflammation. Furthermore, specific polymorphisms in the A20 genomic locus predispose humans to autoimmune disease. Recent studies also indicate that A20 is an important tumor suppressor that is inactivated in B-cell lymphomas. Therefore, targeting A20 may form the basis of novel therapies for autoimmune disease and lymphomas.
基金supported by grants from National Key R&D Program of China(2017YFA0503800)National Natural Science Foundation of China(31330048,31621001)+3 种基金Peking-Tsinghua Center for Life SciencesPeking UniversitySouthern University of Science and TechnologyXiamen University.
文摘Green plants on the earth have evolved intricate mechanisms to acclimatize to and utilize sunlight.In Arabidopsis,light signals are perceived by photoreceptors and transmitted through divergent but overlapping signaling networks to modulate plant photomorphogenic development.COP1(CONSTITUTIVE PHOTOMORPHOGENIC 1)was first cloned as a central repressor of photomorphogenesis in higher plants and has been extensively studied for over 30 years.It acts as a RING E3 ubiquitin ligase downstream of multiple photoreceptors to target key light-signaling regulators for degradation,primarily as part of large protein complexes.The mammalian counterpart of COP1 is a pluripotent regulator of tumorigenesis and metabolism.A great deal of information on COP1 has been derived from whole-genome sequencing and functional studies in lower green plants,which enables us to illustrate its evolutionary history.Here,we reviewthe current understanding about COP1,with a focus on the conservation and functional diversification of COP1 and its signaling partners in different taxonomic clades.
基金This work was supported by the National Science Foundation （NSF grant MCB-1020673 to H.H.）,We would like to thank Sutton Mooney for critical reading and NSF for support （NSF grant MCB-1020673 to H.H.）. No conflict of interest declared.
文摘Since its discovery in the late 1970s, the ubiquitin proteasome pathway appears to be omnipresent in many research fields. Although originally discovered in animals, the pathway has a very central role in plants, which may be correlated to their sessile lifestyle. E3 ligases function as flexible and highly diverse key regulators within the path- way by targeting substrate proteins for ubiquitylation, and often proteolytic degradation via the 26S proteasome. This review provides a concise overview on the most common classes of E3 ligases so far described in plants, and emphasizes recent findings regarding these interesting and flexible enzymes and their diverse functions in plant biology.
文摘Recent discovery of PYR/PYL/RCAR-type abscisic acid （ABA） receptors has become one of most significant advances in plant science in the past decade. In mammals, endosomal sorting acts as an important pathway to downregulate different types of receptors, but its role in plant hormone signaling is poorly understood. Here, we report that an ubiquitin E2-1ike protein, VPS23A, which is a key component of ESCRT-I, negatively regulates ABA signaling. VPS23A has epistatic relationship with PYR/PYL/RCAR-type ABA receptors and disruption of VPS23A enhanced the activity of key kinase OST1 in the ABA signaling pathway under ABA treatment. Moreover, VPS23A interacts with PYR1/PYLs and K63-1inked diubiquitin, and PYL4 possesses K63-1inked ubiquitinated modification in vivo. Further analysis revealed that VPS23A affects the subcellular localization of PYR 1 and the stability of PYL4. Taken together, our results suggest that VPS23A affects PYR1/ PYL4 via vacuole-mediated degradation, providing an advanced understanding of both the turnover of ABA receptors and ESCRTs in plant hormone signaling.
