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Tuberculosis (Tuberculosis, TB) caused by Mycobacterium tuberculosis (M.
tuberculosis, Mtb) infection is an important and fatal chronic infectious disease that seriously threatens global human health.
According to the World Health Organization (WHO), there were about 10 million new TB patients worldwide in 2019, and about 1.
41 million people died of TB.
Mtb is a facultative intracellular parasite, which can use a variety of strategies to interfere with the normal function of host cells to escape the host's immune response, thereby achieving long-term survival in host cells.
Liu Cuihua’s research group at the Institute of Microbiology, Chinese Academy of Sciences has long been committed to the study of new mechanisms for the infection of important pathogens such as Mtb and host immune regulation, especially focusing on the new mechanism by which Mtb hijacks the host ubiquitin system to achieve immune escape and the host ubiquitin system promotes anti-infective innate immune function Molecular mechanism.
In recent years, a series of research works have been published in journals such as Nature Immunology, NatureCommunication, ProcNatl Acad Sci, Cellular & Molecular Immunology, revealing the dynamic process and molecular mechanism of the game between pathogens and hosts, providing new ideas for anti-tuberculosis treatment and drug development And specific targets.
Mtb encodes a series of eukaryotic-like phosphatase/kinase family proteins, among which the eukaryotic-like tyrosine phosphatase PtpA and the eukaryotic-like serine/threonine protein kinase PknG are both secreted effector proteins, and are related to the intracellular survival of Mtb.
The processes are closely related, so Mtb PtpA and Mtb PknG have always been potential important targets for the development of new anti-tuberculosis drugs, but the current specific mechanisms for their regulation of host immune function include related cell biological processes, key signal pathways and targets, and The protein-protein interactions and biochemical regulation mechanisms involved have not yet been fully clarified.Therefore, in-depth study of the molecular mechanism of Mtb PtpA and Mtb PknG interfering with the host immune response will help provide new anti-tuberculosis targets based on the Mtb-host cell interaction interface, and provide new strategies for the development of new types of tuberculosis prevention and treatment drugs and vaccines .
The previous research of Liu Cuihua’s group found that Mtb PtpA interacts with host ubiquitin (Ub), and successively revealed the molecular mechanism of Mtb PtpA by capturing Ub in the cytoplasm to activate its own phosphatase activity to inhibit the host’s innate immune response (NatureImmunology, 2015), and Mtb PtpA promotes tumor cell proliferation in a ubiquitin-independent manner in the nucleus (NatureCommunications, 2017).
Recently, the latest collaborative research between Liu Cuihua's research group and the team of Professor Qiu Xiaobo of Beijing Normal University and the team of Academician Gao Fu of the Institute of Microbiology revealed that Mtb PknG can interact with another key protein of the host ubiquitin system—ubiquitin coupling enzyme (E2) UbcH7 Specific binding occurs and catalyzes a non-classical two-step ubiquitination cascade to target and regulate the host ubiquitin system, thereby inhibiting the host's innate immune response.
Specifically, Mtb PknG has both non-classical ubiquitin activating enzyme (E1) and ubiquitin ligase (E3) activities, and can use its bifunctional enzyme activity to promote tumor necrosis factor receptor-related factor 2 ( TRAF2) and TGF-β activated kinase 1 (TAK1) ubiquitination and degradation, and ultimately inhibit the activation of NF-κB innate immune signaling pathway.
The key innovations and scientific significance of this study are: 1) For the first time, the effector protein PknG with E1 and E3 activity in Mtb and its target host protein substrates (TRAF2 and TAK1) were discovered for the first time.
2) It is revealed that the ubiquitination process regulated by Mtb can be catalyzed by a two-step cascade reaction.
The classic ubiquitination modification is a three-step enzymatic cascade reaction catalyzed by E1, E2 and E3 in turn, while PknG can mediate the ubiquitination modification of the substrate in two steps.
In a one-step reaction, PknG interacts with UbcH7 through its new Ubl domain, and acts as E1 to promote the covalent binding of Ub to UbcH7, and can further utilize its isopeptidase activity to catalyze the dissociation of Ub from the UbcH7-Ub complex To obtain activated Ub.
Interestingly, PknG directly catalyzes the binding of Ub to the Lys82 site of UbcH7 in the form of an isopeptide bond, during which there is no need to form a thioester bond-linked PknG-Ub intermediate, while the classic E1 usually catalyzes the binding of Ub in the form of a thioester bond To the Cys86 site of UbcH7, and the E1-Ub intermediate connected by the thioester bond needs to be formed in between.
In the second step of the reaction, PknG can be used as E3 to transfer the activated Ub to the substrate protein and promote their ubiquitination degradation.
3) Clarified the special energy source of prokaryotes to regulate the host ubiquitination process.
The classical E1 activation process of Ub often uses the hydrolysis of ATP to AMP to provide energy, and the energy that PknG promotes Ub activation comes from the energy released by the hydrolysis of ATP to ADP.
In summary, the innovative results of this research refresh the understanding of the existing ubiquitination catalytic mechanism, reveal a new strategy for pathogens targeting the host ubiquitin system, and provide a new target for anti-tuberculosis treatment based on the pathogen-host interface Point (ie, the Ubl domain related to the non-canonical E1 and E3 enzyme activities of MtbPknG, which has almost no homology with non-pathogenic mycobacteria and host cells) (Figure 1).
Figure 1.
MtbPknG suppresses host innate immunity by catalyzing a non-classical two-step ubiquitination cascade.
Related research results have been published online in the international authoritative journal EMBO reports, entitled "M.
tuberculosis protein kinase G impairs host immunity by acting as an unusualubiquitinating enzyme". Project researcher Wang Jing of Liu Cuihua's research group, PhD student Pupu Pu and master student Lei Zehui are the co-first authors of the paper.
Researcher Liu Cuihua from the Institute of Microbiology, Chinese Academy of Sciences, Professor Qiu Xiaobo from Beijing Normal University, and Academician Gao Fu from the Institute of Microbiology, Chinese Academy of Sciences As the co-corresponding author of this article.
The research was funded by the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences (Category B), the National Key R&D Program Project, the National Science and Technology Major Project, and the Talent Project of the Youth Innovation Promotion Association of the Chinese Academy of Sciences.
Article link: http://doi.
org/10.
15252/embr.
202052175
tuberculosis, Mtb) infection is an important and fatal chronic infectious disease that seriously threatens global human health.
According to the World Health Organization (WHO), there were about 10 million new TB patients worldwide in 2019, and about 1.
41 million people died of TB.
Mtb is a facultative intracellular parasite, which can use a variety of strategies to interfere with the normal function of host cells to escape the host's immune response, thereby achieving long-term survival in host cells.
Liu Cuihua’s research group at the Institute of Microbiology, Chinese Academy of Sciences has long been committed to the study of new mechanisms for the infection of important pathogens such as Mtb and host immune regulation, especially focusing on the new mechanism by which Mtb hijacks the host ubiquitin system to achieve immune escape and the host ubiquitin system promotes anti-infective innate immune function Molecular mechanism.
In recent years, a series of research works have been published in journals such as Nature Immunology, NatureCommunication, ProcNatl Acad Sci, Cellular & Molecular Immunology, revealing the dynamic process and molecular mechanism of the game between pathogens and hosts, providing new ideas for anti-tuberculosis treatment and drug development And specific targets.
Mtb encodes a series of eukaryotic-like phosphatase/kinase family proteins, among which the eukaryotic-like tyrosine phosphatase PtpA and the eukaryotic-like serine/threonine protein kinase PknG are both secreted effector proteins, and are related to the intracellular survival of Mtb.
The processes are closely related, so Mtb PtpA and Mtb PknG have always been potential important targets for the development of new anti-tuberculosis drugs, but the current specific mechanisms for their regulation of host immune function include related cell biological processes, key signal pathways and targets, and The protein-protein interactions and biochemical regulation mechanisms involved have not yet been fully clarified.Therefore, in-depth study of the molecular mechanism of Mtb PtpA and Mtb PknG interfering with the host immune response will help provide new anti-tuberculosis targets based on the Mtb-host cell interaction interface, and provide new strategies for the development of new types of tuberculosis prevention and treatment drugs and vaccines .
The previous research of Liu Cuihua’s group found that Mtb PtpA interacts with host ubiquitin (Ub), and successively revealed the molecular mechanism of Mtb PtpA by capturing Ub in the cytoplasm to activate its own phosphatase activity to inhibit the host’s innate immune response (NatureImmunology, 2015), and Mtb PtpA promotes tumor cell proliferation in a ubiquitin-independent manner in the nucleus (NatureCommunications, 2017).
Recently, the latest collaborative research between Liu Cuihua's research group and the team of Professor Qiu Xiaobo of Beijing Normal University and the team of Academician Gao Fu of the Institute of Microbiology revealed that Mtb PknG can interact with another key protein of the host ubiquitin system—ubiquitin coupling enzyme (E2) UbcH7 Specific binding occurs and catalyzes a non-classical two-step ubiquitination cascade to target and regulate the host ubiquitin system, thereby inhibiting the host's innate immune response.
Specifically, Mtb PknG has both non-classical ubiquitin activating enzyme (E1) and ubiquitin ligase (E3) activities, and can use its bifunctional enzyme activity to promote tumor necrosis factor receptor-related factor 2 ( TRAF2) and TGF-β activated kinase 1 (TAK1) ubiquitination and degradation, and ultimately inhibit the activation of NF-κB innate immune signaling pathway.
The key innovations and scientific significance of this study are: 1) For the first time, the effector protein PknG with E1 and E3 activity in Mtb and its target host protein substrates (TRAF2 and TAK1) were discovered for the first time.
2) It is revealed that the ubiquitination process regulated by Mtb can be catalyzed by a two-step cascade reaction.
The classic ubiquitination modification is a three-step enzymatic cascade reaction catalyzed by E1, E2 and E3 in turn, while PknG can mediate the ubiquitination modification of the substrate in two steps.
In a one-step reaction, PknG interacts with UbcH7 through its new Ubl domain, and acts as E1 to promote the covalent binding of Ub to UbcH7, and can further utilize its isopeptidase activity to catalyze the dissociation of Ub from the UbcH7-Ub complex To obtain activated Ub.
Interestingly, PknG directly catalyzes the binding of Ub to the Lys82 site of UbcH7 in the form of an isopeptide bond, during which there is no need to form a thioester bond-linked PknG-Ub intermediate, while the classic E1 usually catalyzes the binding of Ub in the form of a thioester bond To the Cys86 site of UbcH7, and the E1-Ub intermediate connected by the thioester bond needs to be formed in between.
In the second step of the reaction, PknG can be used as E3 to transfer the activated Ub to the substrate protein and promote their ubiquitination degradation.
3) Clarified the special energy source of prokaryotes to regulate the host ubiquitination process.
The classical E1 activation process of Ub often uses the hydrolysis of ATP to AMP to provide energy, and the energy that PknG promotes Ub activation comes from the energy released by the hydrolysis of ATP to ADP.
In summary, the innovative results of this research refresh the understanding of the existing ubiquitination catalytic mechanism, reveal a new strategy for pathogens targeting the host ubiquitin system, and provide a new target for anti-tuberculosis treatment based on the pathogen-host interface Point (ie, the Ubl domain related to the non-canonical E1 and E3 enzyme activities of MtbPknG, which has almost no homology with non-pathogenic mycobacteria and host cells) (Figure 1).
Figure 1.
MtbPknG suppresses host innate immunity by catalyzing a non-classical two-step ubiquitination cascade.
Related research results have been published online in the international authoritative journal EMBO reports, entitled "M.
tuberculosis protein kinase G impairs host immunity by acting as an unusualubiquitinating enzyme". Project researcher Wang Jing of Liu Cuihua's research group, PhD student Pupu Pu and master student Lei Zehui are the co-first authors of the paper.
Researcher Liu Cuihua from the Institute of Microbiology, Chinese Academy of Sciences, Professor Qiu Xiaobo from Beijing Normal University, and Academician Gao Fu from the Institute of Microbiology, Chinese Academy of Sciences As the co-corresponding author of this article.
The research was funded by the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences (Category B), the National Key R&D Program Project, the National Science and Technology Major Project, and the Talent Project of the Youth Innovation Promotion Association of the Chinese Academy of Sciences.
Article link: http://doi.
org/10.
15252/embr.
202052175
