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The induction of pathogenic nucleic acids by iNature pattern recognition receptor (PRR) will not only activate antimicrobial defenses, but also cause inflammation and autoimmune diseases.
E3 ubiquitin ligase is essential in the innate reaction.
On February 24, 2021, Academician Cao Xuetao of the Suzhou Institute of System Medicine of the Chinese Academy of Medical Sciences and Professor Taoyong Chen of the State Key Laboratory of Medical Immunology jointly published an online report entitled "TRIM41" in the Journal of Signal Transduction and Targeted Therapy (IF=13) is required to innate antiviral response by polyubiquitinating BCL10 and recruiting NEMO" research paper, which reveals that the E3 ubiquitin ligase TRIM41 modifies BCL10 by K63 polyubiquitinating during virus infection of macrophages, and promotes its effect on NEMO and recruiting NEMO.
Recruitment of related kinases, thereby enhancing the antiviral natural immune response.
On the other hand, this study also revealed for the first time that the CBM complex where BCL10 is located can be recruited to the MAVS and STING signal bodies and participate in the antiviral natural immune response after viral infection.
The study discovered new functions, new substrates, and new mechanisms of TRIM41 in the innate immune response, providing new ideas for the treatment of viral infectious diseases and related inflammations.
In addition, on February 24, 2021, the Chinese Academy of Medical Sciences/Peking Union Medical College Jiang Jiandong, Cao Xuetao and Wang Yan jointly published an online publication entitled "Oral berberine improves dopa/dopamine brain levels to Signal Transduction and Targeted Therapy (IF=13)" ameliorate Parkinson's disease by regulating gut microbiota" research paper, which shows that oral berberine (BBR) may provide H• and promote the production of dihydrobiopterin through dihydroberberine (reducing BBR produced by bacterial nitrification reductase) BH4.
The increased BH4 enhances TH activity, thereby accelerating the production of L-dopa by intestinal bacteria.
In short, BBR may up-regulate the biosynthesis of L-dopa in the intestinal flora through a vitamin-like effect, thereby improving brain function (click to read).
On February 5, 2021, Cao Xuetao’s team published an online review article titled "Epigenetic Remodeling in Innate Immunity and Inflammation" in Annual Review of Immunology (IF=20).
The review focused on two aspects: (a) By regulating genes Expression level, gene-specific targeting of enzyme activity or chromatin modifiers, how Niche signals are expressed in cell lineage commitment or infection and pathogenic stress procedures; and (b) programmed epiregulome in turn mediates gene-specific expression This helps to control the development of innate cells or the response to infection and inflammation in a timely manner.
The review will also discuss the impact of innate immune metabolism rewiring on epiregulome, and speculate on some future challenges that will be encountered in the process of exploring epiregulome immunomodulators as major regulators of innate immunity and inflammation (click to read).
The natural immune system is the first line of defense for human beings against external damage and infection.
The prerequisite for the triggering of the innate immune response is the recognition of pathogenic microorganisms by cells, and this process is achieved by identifying pathogen-related molecular patterns (PAMPs) through pattern recognition receptors (PRRs).
Antiviral immunity is an important part of the natural immune system.
In today's raging new coronavirus epidemic, it is the molecular mechanism of immunology to study how natural immune cells can sensitively and specifically recognize viral infections and induce type I interferon to clear the virus.
One of the important scientific issues.
Nucleic acid receptors (including DNA and RNA receptors) are the main pattern recognition receptors that mediate antiviral immunity.
Macrophages can recognize nucleic acid components of invading viruses through nucleic acid receptors located in cells such as cGAS and RIG-I.
Sting, Mavs and other adaptor proteins promote the production of type I interferon and inflammatory factors to help the body resist viral infections.
However, whether the body still has new molecules and mechanisms to regulate the antiviral natural immune response is worthy of further exploration.
Like phosphorylation, ubiquitination modification is one of the most important post-translational modifications of proteins.
They can be modified by different types of ubiquitination of substrate proteins (such as monoubiquitination, polyubiquitination, and polyubiquitination).
Polyubiquitination) in order to regulate the function of the substrate protein.
In the past, a large number of studies have shown that ubiquitination modification can regulate natural immunity and acquired immune response through a variety of mechanisms.
Ubiquitination modification is a cascade of enzymatic reactions.
In this process, the E3 ubiquitin ligase has the function of specifically recognizing substrates and has become a hot spot and focus of ubiquitination modification research.
Due to the largeness of the members of the E3 ubiquitin ligase family and the precision and complexity of signal transduction regulation, the regulatory function of ubiquitination modification in the antiviral natural immune response is still worthy of our in-depth study.
CARD protein (caspaserecruitment domain)-BCL10 (B cell lymphoma 10)-MALT1 (mucosa-associated-lymphoid tissue lymphoma-translocation gene 1) signaling complex, also known as CBM complex, which can regulate multiple receptors (mainly (TCR/BCR receptor) downstream NF-κB signal activation.
However, it is still poorly understood whether the CBM complex plays a regulatory function downstream of PRR receptors, especially intracellular nucleic acid receptors.
In the CBM complex, BCL10, as one of the scaffolds assembled by the CBM complex, plays an important role in the activation of IKK and NF-κB.
Previous studies have shown that the post-translational modification of BCL10 may be a potential mechanism for its regulatory function.
The activation of TCR can phosphorylate BCL10, which can regulate the activation of IKK and NF-κB.
On the other hand, it has been confirmed that BCL10 can also be ubiquitinated after TCR downstream signal activation, and play an important role in the subsequent activation of NF-κB.
However, during the natural immune response, whether BCL10 will undergo ubiquitination, whether its ubiquitination has a regulatory function, and the E3 ubiquitin ligase that mediates BCL10 ubiquitination is unknown.
In the preliminary study of this project, the researchers used the VSV infection macrophage model and gene chip technology to analyze the E3 ubiquitin ligase that is responsive to VSV infection, and used small RNA interference technology to treat these E3 in antiviral natural immunity The response function was screened and it was found that interference with TRIM41 can inhibit the production of IL-6, TNF-α and IFNβ mediated by RNA virus VSV and DNA virus HSV in macrophages.
Therefore, the researchers constructed a knockout mouse of TRIM41 and studied its function in the antiviral natural immune response.
In the mouse bone marrow-derived macrophages knocked out of TRIM41, the IL-6, TNF-α and IFNβ induced by the increase of nucleic acid analogs, related viruses, bacteria and self-nucleic acid were all significantly reduced.
In TRIM41 knockout mice, the levels of inflammatory factors and interferons induced by VSV, HSV-1 and Listeria are lower, and there are fewer liver damage and inflammatory changes, but the pathogens are in the tissues and organs of TRIM41 knockout mice.
The stronger growth ability in the mouse leads to a significantly shorter survival period of the mice.
The above results prove that TRIM41 can promote antiviral innate immune response.
In order to study the mechanism of TRIM41 exerting its antiviral effect, the research team first conducted a luciferase reporter gene experiment.
The results suggested that TRIM41 can promote the activation of key antiviral adaptor proteins MAVS and STING-mediated NF-κB and IFNβ reporter genes.
Signal pathway studies have found that TRIM41 can promote the activation of NF-κB, JNK, p38 and TBK1-IRF3 signals.
Subsequently, the researchers used immunoprecipitation, mass spectrometry, GST pulldown, fluorescence confocal technology and in vitro ubiquitination research system to confirm from different angles, after the virus stimulates macrophages, TRIM41 can pass through its PRY-SPRY domain and BCL10 The CARD domain of BCL10 directly binds and can promote the K63 polyubiquitination modification of BCL10.
This key modification can promote the recruitment of BCL10 to NEMO.
Recent studies have confirmed that after the virus stimulates macrophages, the key antiviral adapter proteins MAVS and STING can recruit CARD protein and BCL10, and TRIM41 can promote MAVS and STING to NEMO and its related IKK signaling complexes, TAK1, and BCL10 through BCL10.
The recruitment of TBK1 mediates the activation of downstream signals of nucleic acid receptors and promotes the production of inflammatory factors and interferons. Finally, the researchers used CRISPER/CAS9 technology to construct BCL10 and NEMO knock-out RAW264.
7 cell lines, and at the same time constructed BCL10 K31/K63 site and NEMO ubiquitin binding site mutants, and used knock-out and rescue Experiments have confirmed that the K63 polyubiquitination modification of BCL10 K31/K63 and the binding ability of NEMO to the K63 polyubiquitin chain are crucial for the generation of TRIM41 antiviral effect and the assembly of the downstream signal complex of MAVS and STING.
of.
This result suggests that TRIM41's function of promoting antiviral innate immune response depends on BCL1O and NEMO.
In summary, the study has the following two innovative findings: 1: It is the first report that TRIM41 can promote the K63 polyubiquitination modification of BCL10 and its recruitment of NEMO in macrophages to promote RIG-I/MAVS, cGAS/ The activation of downstream signals of STING promotes the innate immune response against RNA and DNA viruses.
At the same time, it is the first time to find evidence that BCL10 participates in the innate immune response and the key E3 ubiquitin ligase that mediates its ubiquitination modification in this process.
2: It is proved that the CBM complex participates in the composition and activation of the downstream signal complex of the innate immune nucleic acid receptor, which enriches the function of the CBM complex in macrophages.
This research provides a new theoretical basis for the intervention of anti-infection immunity and inflammation-related diseases.
The co-corresponding authors of the paper are Academician Cao Xuetao of the Suzhou Institute of System Medicine of the Chinese Academy of Medical Sciences and Professor Taoyong Chen of the State Key Laboratory of Medical Immunology.
Associate researcher Yu Zhou of the Suzhou Institute of System Medicine of the Chinese Academy of Medical Sciences is the first author.
Zhejiang Dr.
Xuelian Li from the Institute of Immunology at the University School of Medicine and Associate Professor Mingjin Yang from the State Key Laboratory of Medical Immunology are the co-first authors.
This research was funded by the National Natural Science Foundation of China, the Medical and Health Innovation Project of the Chinese Academy of Medical Sciences, and the National Key Research and Development Program.
Reference message: https://
E3 ubiquitin ligase is essential in the innate reaction.
On February 24, 2021, Academician Cao Xuetao of the Suzhou Institute of System Medicine of the Chinese Academy of Medical Sciences and Professor Taoyong Chen of the State Key Laboratory of Medical Immunology jointly published an online report entitled "TRIM41" in the Journal of Signal Transduction and Targeted Therapy (IF=13) is required to innate antiviral response by polyubiquitinating BCL10 and recruiting NEMO" research paper, which reveals that the E3 ubiquitin ligase TRIM41 modifies BCL10 by K63 polyubiquitinating during virus infection of macrophages, and promotes its effect on NEMO and recruiting NEMO.
Recruitment of related kinases, thereby enhancing the antiviral natural immune response.
On the other hand, this study also revealed for the first time that the CBM complex where BCL10 is located can be recruited to the MAVS and STING signal bodies and participate in the antiviral natural immune response after viral infection.
The study discovered new functions, new substrates, and new mechanisms of TRIM41 in the innate immune response, providing new ideas for the treatment of viral infectious diseases and related inflammations.
In addition, on February 24, 2021, the Chinese Academy of Medical Sciences/Peking Union Medical College Jiang Jiandong, Cao Xuetao and Wang Yan jointly published an online publication entitled "Oral berberine improves dopa/dopamine brain levels to Signal Transduction and Targeted Therapy (IF=13)" ameliorate Parkinson's disease by regulating gut microbiota" research paper, which shows that oral berberine (BBR) may provide H• and promote the production of dihydrobiopterin through dihydroberberine (reducing BBR produced by bacterial nitrification reductase) BH4.
The increased BH4 enhances TH activity, thereby accelerating the production of L-dopa by intestinal bacteria.
In short, BBR may up-regulate the biosynthesis of L-dopa in the intestinal flora through a vitamin-like effect, thereby improving brain function (click to read).
On February 5, 2021, Cao Xuetao’s team published an online review article titled "Epigenetic Remodeling in Innate Immunity and Inflammation" in Annual Review of Immunology (IF=20).
The review focused on two aspects: (a) By regulating genes Expression level, gene-specific targeting of enzyme activity or chromatin modifiers, how Niche signals are expressed in cell lineage commitment or infection and pathogenic stress procedures; and (b) programmed epiregulome in turn mediates gene-specific expression This helps to control the development of innate cells or the response to infection and inflammation in a timely manner.
The review will also discuss the impact of innate immune metabolism rewiring on epiregulome, and speculate on some future challenges that will be encountered in the process of exploring epiregulome immunomodulators as major regulators of innate immunity and inflammation (click to read).
The natural immune system is the first line of defense for human beings against external damage and infection.
The prerequisite for the triggering of the innate immune response is the recognition of pathogenic microorganisms by cells, and this process is achieved by identifying pathogen-related molecular patterns (PAMPs) through pattern recognition receptors (PRRs).
Antiviral immunity is an important part of the natural immune system.
In today's raging new coronavirus epidemic, it is the molecular mechanism of immunology to study how natural immune cells can sensitively and specifically recognize viral infections and induce type I interferon to clear the virus.
One of the important scientific issues.
Nucleic acid receptors (including DNA and RNA receptors) are the main pattern recognition receptors that mediate antiviral immunity.
Macrophages can recognize nucleic acid components of invading viruses through nucleic acid receptors located in cells such as cGAS and RIG-I.
Sting, Mavs and other adaptor proteins promote the production of type I interferon and inflammatory factors to help the body resist viral infections.
However, whether the body still has new molecules and mechanisms to regulate the antiviral natural immune response is worthy of further exploration.
Like phosphorylation, ubiquitination modification is one of the most important post-translational modifications of proteins.
They can be modified by different types of ubiquitination of substrate proteins (such as monoubiquitination, polyubiquitination, and polyubiquitination).
Polyubiquitination) in order to regulate the function of the substrate protein.
In the past, a large number of studies have shown that ubiquitination modification can regulate natural immunity and acquired immune response through a variety of mechanisms.
Ubiquitination modification is a cascade of enzymatic reactions.
In this process, the E3 ubiquitin ligase has the function of specifically recognizing substrates and has become a hot spot and focus of ubiquitination modification research.
Due to the largeness of the members of the E3 ubiquitin ligase family and the precision and complexity of signal transduction regulation, the regulatory function of ubiquitination modification in the antiviral natural immune response is still worthy of our in-depth study.
CARD protein (caspaserecruitment domain)-BCL10 (B cell lymphoma 10)-MALT1 (mucosa-associated-lymphoid tissue lymphoma-translocation gene 1) signaling complex, also known as CBM complex, which can regulate multiple receptors (mainly (TCR/BCR receptor) downstream NF-κB signal activation.
However, it is still poorly understood whether the CBM complex plays a regulatory function downstream of PRR receptors, especially intracellular nucleic acid receptors.
In the CBM complex, BCL10, as one of the scaffolds assembled by the CBM complex, plays an important role in the activation of IKK and NF-κB.
Previous studies have shown that the post-translational modification of BCL10 may be a potential mechanism for its regulatory function.
The activation of TCR can phosphorylate BCL10, which can regulate the activation of IKK and NF-κB.
On the other hand, it has been confirmed that BCL10 can also be ubiquitinated after TCR downstream signal activation, and play an important role in the subsequent activation of NF-κB.
However, during the natural immune response, whether BCL10 will undergo ubiquitination, whether its ubiquitination has a regulatory function, and the E3 ubiquitin ligase that mediates BCL10 ubiquitination is unknown.
In the preliminary study of this project, the researchers used the VSV infection macrophage model and gene chip technology to analyze the E3 ubiquitin ligase that is responsive to VSV infection, and used small RNA interference technology to treat these E3 in antiviral natural immunity The response function was screened and it was found that interference with TRIM41 can inhibit the production of IL-6, TNF-α and IFNβ mediated by RNA virus VSV and DNA virus HSV in macrophages.
Therefore, the researchers constructed a knockout mouse of TRIM41 and studied its function in the antiviral natural immune response.
In the mouse bone marrow-derived macrophages knocked out of TRIM41, the IL-6, TNF-α and IFNβ induced by the increase of nucleic acid analogs, related viruses, bacteria and self-nucleic acid were all significantly reduced.
In TRIM41 knockout mice, the levels of inflammatory factors and interferons induced by VSV, HSV-1 and Listeria are lower, and there are fewer liver damage and inflammatory changes, but the pathogens are in the tissues and organs of TRIM41 knockout mice.
The stronger growth ability in the mouse leads to a significantly shorter survival period of the mice.
The above results prove that TRIM41 can promote antiviral innate immune response.
In order to study the mechanism of TRIM41 exerting its antiviral effect, the research team first conducted a luciferase reporter gene experiment.
The results suggested that TRIM41 can promote the activation of key antiviral adaptor proteins MAVS and STING-mediated NF-κB and IFNβ reporter genes.
Signal pathway studies have found that TRIM41 can promote the activation of NF-κB, JNK, p38 and TBK1-IRF3 signals.
Subsequently, the researchers used immunoprecipitation, mass spectrometry, GST pulldown, fluorescence confocal technology and in vitro ubiquitination research system to confirm from different angles, after the virus stimulates macrophages, TRIM41 can pass through its PRY-SPRY domain and BCL10 The CARD domain of BCL10 directly binds and can promote the K63 polyubiquitination modification of BCL10.
This key modification can promote the recruitment of BCL10 to NEMO.
Recent studies have confirmed that after the virus stimulates macrophages, the key antiviral adapter proteins MAVS and STING can recruit CARD protein and BCL10, and TRIM41 can promote MAVS and STING to NEMO and its related IKK signaling complexes, TAK1, and BCL10 through BCL10.
The recruitment of TBK1 mediates the activation of downstream signals of nucleic acid receptors and promotes the production of inflammatory factors and interferons. Finally, the researchers used CRISPER/CAS9 technology to construct BCL10 and NEMO knock-out RAW264.
7 cell lines, and at the same time constructed BCL10 K31/K63 site and NEMO ubiquitin binding site mutants, and used knock-out and rescue Experiments have confirmed that the K63 polyubiquitination modification of BCL10 K31/K63 and the binding ability of NEMO to the K63 polyubiquitin chain are crucial for the generation of TRIM41 antiviral effect and the assembly of the downstream signal complex of MAVS and STING.
of.
This result suggests that TRIM41's function of promoting antiviral innate immune response depends on BCL1O and NEMO.
In summary, the study has the following two innovative findings: 1: It is the first report that TRIM41 can promote the K63 polyubiquitination modification of BCL10 and its recruitment of NEMO in macrophages to promote RIG-I/MAVS, cGAS/ The activation of downstream signals of STING promotes the innate immune response against RNA and DNA viruses.
At the same time, it is the first time to find evidence that BCL10 participates in the innate immune response and the key E3 ubiquitin ligase that mediates its ubiquitination modification in this process.
2: It is proved that the CBM complex participates in the composition and activation of the downstream signal complex of the innate immune nucleic acid receptor, which enriches the function of the CBM complex in macrophages.
This research provides a new theoretical basis for the intervention of anti-infection immunity and inflammation-related diseases.
The co-corresponding authors of the paper are Academician Cao Xuetao of the Suzhou Institute of System Medicine of the Chinese Academy of Medical Sciences and Professor Taoyong Chen of the State Key Laboratory of Medical Immunology.
Associate researcher Yu Zhou of the Suzhou Institute of System Medicine of the Chinese Academy of Medical Sciences is the first author.
Zhejiang Dr.
Xuelian Li from the Institute of Immunology at the University School of Medicine and Associate Professor Mingjin Yang from the State Key Laboratory of Medical Immunology are the co-first authors.
This research was funded by the National Natural Science Foundation of China, the Medical and Health Innovation Project of the Chinese Academy of Medical Sciences, and the National Key Research and Development Program.
Reference message: https://
