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Written by | Xueyue T cell-mediated adaptive immune response is essential for the body to fight pathogens and tumors
.
T cell activation requires TCR signals, costimulatory molecules and cytokines to work together
.
Studies have shown that nutrients can also regulate the immune response of conventional T cells and Treg cells
.
Nutrients can interact with immune signals to activate mTORC1
.
mTORC1 is a key driver of cell metabolism
.
However, how environmental signals integrate and participate in immune response regulation is still unclear
.
The nutrient transporters and the regulation and signaling mechanisms of receptors have not yet been elucidated
.
Recently, Hongbo Chi from the St.
Jude Children’s Research Hospital in the United States published an article titled CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity in Nature
.
Through CRISPR screening, the authors constructed the mTORC1 regulatory network in T cells, elucidating the connection between nutritional signals and immune signals
.
The author first established a screening library for mTORC1 activity regulation analysis by measuring mTORC1-dependent ribosomal protein S6 phosphorylation
.
The author selected Th1 and Treg that were induced to differentiate for experiments
.
Analysis found that nutrients can induce TCR-mediated pS6 activation in Treg
.
In the absence of amino acids or glucose, TCR-induced mTORC1 activation and Treg cell proliferation are significantly inhibited
.
Therefore, the author chose Treg for screening
.
Through the genome-wide lentiviral CRISPR library screening, the authors found 292 positive regulators of mTORC1, including the known GATOR2 (SEC13, MIOS, SEH1L, WDR24 and WDR59 and 125 negative regulators, including the known TSC1/2 And GATOR1) NPRL2, NPRL3 and DEPDC5
.
The author conducted a second CRISPR screening for these 417 genes, and 83% of the genes had the same results in the two screenings
.
Next, the author used the two-color culture system to detect the influence of candidate genes on cell endogenousness, and verified 63 positive regulatory proteins and 21 negative regulatory proteins of mTORC1
.
The author also performed a functional enrichment analysis of 346 mTORC1 regulatory proteins and found enrichment in a variety of mTORC1 signal transduction processes
.
And combined with the PPI database analysis to determine a number of functional modules
.
One of the modules contains SWI/SNF complex components
.
The author's verification and summary found that SWI/SNF complex inhibits Castor1 to promote mTORC1 activation in Treg
.
There is also a functional module with multiple GATOR1 and GATOR2 components and SEC31A
.
Validation found that the deletion of SEC31A inhibits amino acid or glucose-mediated mTORC1 activation
.
Therefore, SEC31A is essential for integrating nutritional and immune signals to activate mTORC1
.
The author next analyzed the epistasis of SEC31A and the established mTORC1 regulatory protein
.
The authors found that SEC31A and SEC13 destroyed the integrity of the GATOR2 complex and reduced the interaction of WDR24 with other GATOR2 components
.
Further analysis found that SEC31A can inhibit SKP1-dependent SEC13 ubiquitination and proteasome degradation, thereby promoting mTORC1 activation
.
On the other hand, the author also explored the mechanism of inhibiting mTORC1 activity
.
The authors found that CCDC101 can inhibit the expression of nutrient transporters such as GLUT1 and downstream signals of GATOR2-RAGA, thereby limiting mTORC1 activation to maintain T cell function homeostasis and lineage stability
.
Finally, the authors constructed mice with Treg-specific knockout of CCDC101 to explore the functions of CCDC101 in vivo
.
The analysis found that the immune homeostasis of the mice that knocked out CCDC101 was changed and spontaneous inflammation occurred
.
Knockout of CCDC101 in tumor models will increase the ratio of IFNg+ and TNF+CF8T+ cells
.
Therefore, CCDC101 is essential for maintaining Treg cell function and tumor suppressor function
.
This paper systematically identified the regulatory network of mTORC1 signaling in T cells
.
This article establishes a connection between immune signals and nutritional signals, and expands the emerging concept of bidirectional metabolic signals in adaptive immune responses
.
The identification of the mTORC1 signal transduction module provides a mechanism basis for nutritional signal-related targeted therapy in infectious diseases and other immune-mediated diseases
.
Original link: https://doi.
org/10.
1038/s41586-021-04109-7 Plate maker: Instructions for reprinting on the 11th [Original article] BioArt original article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
.
T cell activation requires TCR signals, costimulatory molecules and cytokines to work together
.
Studies have shown that nutrients can also regulate the immune response of conventional T cells and Treg cells
.
Nutrients can interact with immune signals to activate mTORC1
.
mTORC1 is a key driver of cell metabolism
.
However, how environmental signals integrate and participate in immune response regulation is still unclear
.
The nutrient transporters and the regulation and signaling mechanisms of receptors have not yet been elucidated
.
Recently, Hongbo Chi from the St.
Jude Children’s Research Hospital in the United States published an article titled CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity in Nature
.
Through CRISPR screening, the authors constructed the mTORC1 regulatory network in T cells, elucidating the connection between nutritional signals and immune signals
.
The author first established a screening library for mTORC1 activity regulation analysis by measuring mTORC1-dependent ribosomal protein S6 phosphorylation
.
The author selected Th1 and Treg that were induced to differentiate for experiments
.
Analysis found that nutrients can induce TCR-mediated pS6 activation in Treg
.
In the absence of amino acids or glucose, TCR-induced mTORC1 activation and Treg cell proliferation are significantly inhibited
.
Therefore, the author chose Treg for screening
.
Through the genome-wide lentiviral CRISPR library screening, the authors found 292 positive regulators of mTORC1, including the known GATOR2 (SEC13, MIOS, SEH1L, WDR24 and WDR59 and 125 negative regulators, including the known TSC1/2 And GATOR1) NPRL2, NPRL3 and DEPDC5
.
The author conducted a second CRISPR screening for these 417 genes, and 83% of the genes had the same results in the two screenings
.
Next, the author used the two-color culture system to detect the influence of candidate genes on cell endogenousness, and verified 63 positive regulatory proteins and 21 negative regulatory proteins of mTORC1
.
The author also performed a functional enrichment analysis of 346 mTORC1 regulatory proteins and found enrichment in a variety of mTORC1 signal transduction processes
.
And combined with the PPI database analysis to determine a number of functional modules
.
One of the modules contains SWI/SNF complex components
.
The author's verification and summary found that SWI/SNF complex inhibits Castor1 to promote mTORC1 activation in Treg
.
There is also a functional module with multiple GATOR1 and GATOR2 components and SEC31A
.
Validation found that the deletion of SEC31A inhibits amino acid or glucose-mediated mTORC1 activation
.
Therefore, SEC31A is essential for integrating nutritional and immune signals to activate mTORC1
.
The author next analyzed the epistasis of SEC31A and the established mTORC1 regulatory protein
.
The authors found that SEC31A and SEC13 destroyed the integrity of the GATOR2 complex and reduced the interaction of WDR24 with other GATOR2 components
.
Further analysis found that SEC31A can inhibit SKP1-dependent SEC13 ubiquitination and proteasome degradation, thereby promoting mTORC1 activation
.
On the other hand, the author also explored the mechanism of inhibiting mTORC1 activity
.
The authors found that CCDC101 can inhibit the expression of nutrient transporters such as GLUT1 and downstream signals of GATOR2-RAGA, thereby limiting mTORC1 activation to maintain T cell function homeostasis and lineage stability
.
Finally, the authors constructed mice with Treg-specific knockout of CCDC101 to explore the functions of CCDC101 in vivo
.
The analysis found that the immune homeostasis of the mice that knocked out CCDC101 was changed and spontaneous inflammation occurred
.
Knockout of CCDC101 in tumor models will increase the ratio of IFNg+ and TNF+CF8T+ cells
.
Therefore, CCDC101 is essential for maintaining Treg cell function and tumor suppressor function
.
This paper systematically identified the regulatory network of mTORC1 signaling in T cells
.
This article establishes a connection between immune signals and nutritional signals, and expands the emerging concept of bidirectional metabolic signals in adaptive immune responses
.
The identification of the mTORC1 signal transduction module provides a mechanism basis for nutritional signal-related targeted therapy in infectious diseases and other immune-mediated diseases
.
Original link: https://doi.
org/10.
1038/s41586-021-04109-7 Plate maker: Instructions for reprinting on the 11th [Original article] BioArt original article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
