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Recently, the research group of Xiao Yichuan, a researcher at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, and Zheng Mingyue, a researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, published an online publication titled Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation on Immunity.
and aging-related autoimmune inflammation.
This study reveals that the KU complex mediates DNA perception in CD4+ T cells, which in turn mediates the regulatory mechanism of aging-related autoimmune diseases.
The aging of the population is a major social problem facing my country and the world at present.
With the increase of age, the normal body appears to be aging, and the aging of the immune system is one of the prominent and important problems, and it is also prone to chronic inflammation in elderly individuals.
An important cause of autoimmune diseases.
T cell-mediated adaptive immunity is a key driving force for the body to induce autoimmune inflammation.
Although thymus atrophy caused by aging will reduce the initial T cell output, the number of peripheral T cells in the elderly does not decrease.
The reason is Peripheral T cells will undergo steady-state proliferation and activation in the state of senescence.
However, the academic community is still not clear about the specific regulatory mechanism that aging induces the steady-state proliferation of T cells and promotes the occurrence and development of autoimmune inflammation.
The study found that there is a large amount of DNA accumulation in the cytoplasm of CD4+ T cells in old mice and humans, and this accumulated DNA will promote the proliferation and activation of CD4+ T cells induced by TCR, indicating that T cells themselves can sense through DNA And promote its functional activation.
The researchers found that the cytoplasmic DNA in T cells is not bound to cGAS, but to the KU complex (KU70/KU80) through mass spectrometry combined with western blotting.
If the small molecule inhibitor STL127705 is used to block the binding of KU complex to DNA, it will significantly inhibit the proliferation and activation of CD4+ T cells induced by DNA, thereby alleviating the occurrence and development of autoimmune inflammation in old mice, indicating that DNA-induced T cell function activation is indeed mediated by DNA sensing through the KU complex.
Further studies have found that the KU complex is expressed in large amounts in the cytoplasm of T cells.
After recognizing DNA in CD4+ T cells, it can promote the phosphorylation and activation of DNA-PKcs, which in turn mediates the phosphorylation of T169 of ZAK and activates ZAK.
Then phosphorylate AKT to activate the downstream mTOR pathway, thereby enhancing the proliferation and activation of CD4+ T cells.
Therefore, the activation of the DNA sensing pathway mediated by the KU complex in CD4+ T cells is the key mechanism leading to the development of autoimmune inflammation in aged mice.
In order to explore therapeutic strategies to interfere with this newly discovered DNA sensing pathway to suppress aging-related autoimmune inflammation, the researchers used calorie restriction (CR) or simulated intermittent feeding (FMD) to treat elderly mice and found these two dieting patterns Both can significantly reduce the DNA damage and cytoplasmic DNA accumulation of CD4+ T cells in old mice, thereby inhibiting the phosphorylation of ZAK-T169 and the activation of downstream AKT/mTOR signals, and finally inhibiting the activation of CD4+ T cells and aging-related self Symptoms of immune disease.
Furthermore, based on the key protein kinase ZAK identified in the DNA sensing pathway, the researchers used deep learning combined with molecular simulation methods to screen from approximately 130,000 compound libraries to obtain a small molecule compound iZAK2 that can specifically inhibit the activity of ZAK kinase.
It was found that iZAK2 can effectively inhibit DNA-induced CD4+ T cell proliferation and activation, thereby alleviating the pathological symptoms of autoimmune diseases in elderly mice.
In summary, this study revealed that cGAS/STING-independent DNA sensing signaling pathways in senescent CD4+ T cells can promote the activation and proliferation of T cells and lead to the occurrence and development of aging-related autoimmune diseases.
Further research and development of inhibitors that block DNA sensing signal transduction in T cells may be beneficial for clinical treatment of aging-related autoimmune diseases.
Doctoral student Wang Yan of the Institute of Nutrition and Health is the first author of the paper, and Xiao Yichuan and Zheng Mingyue are the co-corresponding authors of the paper.
The research work was carried out by Professor Shu Hongbing and Zhong Bo of Wuhan University, Professor Li Tao of the National Center for Protein Science (Beijing), Professor Xu Pinglong of Zhejiang University, Professor Xiao Hui of the Shanghai Pasteur Institute of the Chinese Academy of Sciences, Professor Ge Baoxue of Tongji University, and Professor Chang Xing of West Lake University.
Help, get funding from the Ministry of Science and Technology, the National Natural Science Foundation of China, the Chinese Academy of Sciences and other projects, and get the support of the public technology platform and animal platform of the Institute of Nutrition and Health.
Schematic diagram of the cartoon and mechanism of DNA sensing in aging CD4+ T cells to promote their activation and autoimmune inflammation.
Link to the paper: https:// Hot Wenjing Choose 1.
Cup! A full paper cup of hot coffee, full of plastic particles.
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2.
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3.
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5.
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6.
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7.
Junk food is "real rubbish"! It takes away telomere length and makes people grow old faster! 8.
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.
9.
The ultra-large-scale study of "Nature Communications": The level of iron in the blood is the key to health and aging! 10.
Unbelievable! Scientists reversed the "permanent" brain damage in animals overnight, and restored the old brain to a young state.
.
.
and aging-related autoimmune inflammation.
This study reveals that the KU complex mediates DNA perception in CD4+ T cells, which in turn mediates the regulatory mechanism of aging-related autoimmune diseases.
The aging of the population is a major social problem facing my country and the world at present.
With the increase of age, the normal body appears to be aging, and the aging of the immune system is one of the prominent and important problems, and it is also prone to chronic inflammation in elderly individuals.
An important cause of autoimmune diseases.
T cell-mediated adaptive immunity is a key driving force for the body to induce autoimmune inflammation.
Although thymus atrophy caused by aging will reduce the initial T cell output, the number of peripheral T cells in the elderly does not decrease.
The reason is Peripheral T cells will undergo steady-state proliferation and activation in the state of senescence.
However, the academic community is still not clear about the specific regulatory mechanism that aging induces the steady-state proliferation of T cells and promotes the occurrence and development of autoimmune inflammation.
The study found that there is a large amount of DNA accumulation in the cytoplasm of CD4+ T cells in old mice and humans, and this accumulated DNA will promote the proliferation and activation of CD4+ T cells induced by TCR, indicating that T cells themselves can sense through DNA And promote its functional activation.
The researchers found that the cytoplasmic DNA in T cells is not bound to cGAS, but to the KU complex (KU70/KU80) through mass spectrometry combined with western blotting.
If the small molecule inhibitor STL127705 is used to block the binding of KU complex to DNA, it will significantly inhibit the proliferation and activation of CD4+ T cells induced by DNA, thereby alleviating the occurrence and development of autoimmune inflammation in old mice, indicating that DNA-induced T cell function activation is indeed mediated by DNA sensing through the KU complex.
Further studies have found that the KU complex is expressed in large amounts in the cytoplasm of T cells.
After recognizing DNA in CD4+ T cells, it can promote the phosphorylation and activation of DNA-PKcs, which in turn mediates the phosphorylation of T169 of ZAK and activates ZAK.
Then phosphorylate AKT to activate the downstream mTOR pathway, thereby enhancing the proliferation and activation of CD4+ T cells.
Therefore, the activation of the DNA sensing pathway mediated by the KU complex in CD4+ T cells is the key mechanism leading to the development of autoimmune inflammation in aged mice.
In order to explore therapeutic strategies to interfere with this newly discovered DNA sensing pathway to suppress aging-related autoimmune inflammation, the researchers used calorie restriction (CR) or simulated intermittent feeding (FMD) to treat elderly mice and found these two dieting patterns Both can significantly reduce the DNA damage and cytoplasmic DNA accumulation of CD4+ T cells in old mice, thereby inhibiting the phosphorylation of ZAK-T169 and the activation of downstream AKT/mTOR signals, and finally inhibiting the activation of CD4+ T cells and aging-related self Symptoms of immune disease.
Furthermore, based on the key protein kinase ZAK identified in the DNA sensing pathway, the researchers used deep learning combined with molecular simulation methods to screen from approximately 130,000 compound libraries to obtain a small molecule compound iZAK2 that can specifically inhibit the activity of ZAK kinase.
It was found that iZAK2 can effectively inhibit DNA-induced CD4+ T cell proliferation and activation, thereby alleviating the pathological symptoms of autoimmune diseases in elderly mice.
In summary, this study revealed that cGAS/STING-independent DNA sensing signaling pathways in senescent CD4+ T cells can promote the activation and proliferation of T cells and lead to the occurrence and development of aging-related autoimmune diseases.
Further research and development of inhibitors that block DNA sensing signal transduction in T cells may be beneficial for clinical treatment of aging-related autoimmune diseases.
Doctoral student Wang Yan of the Institute of Nutrition and Health is the first author of the paper, and Xiao Yichuan and Zheng Mingyue are the co-corresponding authors of the paper.
The research work was carried out by Professor Shu Hongbing and Zhong Bo of Wuhan University, Professor Li Tao of the National Center for Protein Science (Beijing), Professor Xu Pinglong of Zhejiang University, Professor Xiao Hui of the Shanghai Pasteur Institute of the Chinese Academy of Sciences, Professor Ge Baoxue of Tongji University, and Professor Chang Xing of West Lake University.
Help, get funding from the Ministry of Science and Technology, the National Natural Science Foundation of China, the Chinese Academy of Sciences and other projects, and get the support of the public technology platform and animal platform of the Institute of Nutrition and Health.
Schematic diagram of the cartoon and mechanism of DNA sensing in aging CD4+ T cells to promote their activation and autoimmune inflammation.
Link to the paper: https:// Hot Wenjing Choose 1.
Cup! A full paper cup of hot coffee, full of plastic particles.
.
.
2.
Scientists from the United States, Britain and Australia “Natural Medicine” further prove that the new coronavirus is a natural evolution product, or has two origins.
.
.
3.
NEJM: Intermittent fasting is right The impact of health, aging and disease 4.
Heal insomnia within one year! The study found that: to improve sleep, you may only need a heavy blanket.
5.
New Harvard study: Only 12 minutes of vigorous exercise can bring huge metabolic benefits to health.
6.
The first human intervention experiment: in nature.
"Feeling and rolling" for 28 days is enough to improve immunity.
7.
Junk food is "real rubbish"! It takes away telomere length and makes people grow old faster! 8.
Cell puzzle: you can really die if you don't sleep! But the fatal changes do not occur in the brain, but in the intestines.
.
.
9.
The ultra-large-scale study of "Nature Communications": The level of iron in the blood is the key to health and aging! 10.
Unbelievable! Scientists reversed the "permanent" brain damage in animals overnight, and restored the old brain to a young state.
.
.
