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Editor | T6SS (type VI secretion system) is one of the current research hotspots in the field of microorganisms
.
As a widely distributed secretion system with complex structure, T6SS can deliver different types of effector proteins to the extracellular environment, other bacteria or host cells, so as to resist environmental stress, competition between bacteria and interaction with the host.
Play an important role [1, 2]
.
Innate immunity is the host's first line of defense against the invasion of pathogenic microorganisms.
The cGAS-STING signaling pathway plays an important role in the host's fight against a variety of viral and bacterial infections
.
In 2018, Professor Jiang Zhengfan’s laboratory revealed that manganese ions play an important role in cellular antiviral natural immunity by activating cGAS-STING [3]
.
Previous research by Professor Shen Xihui’s laboratory found that Burkholderia thailandensis T6SS mediates the transport of manganese ions by secreting a manganese ion-binding effector protein TseM, thereby promoting the anti-oxidative stress and pathogenicity of the bacteria.
【4】
.
These findings prompted them to further explore whether this type of T6SS effector protein with manganese ion binding function can regulate the host's natural immunity by affecting the manganese ion level in the host cell
.
On October 4, 2021, the laboratory of Professor Xihui Shen of Northwest A&F University cooperated with the laboratory of Professor Jiang Zhengfan of the Beijing University of Science and Technology and the laboratory of Researcher Zhou Dongsheng of the Academy of Military Medical Sciences to publish the paper T6SS translocates a micropeptide to suppress STING-mediated innate immunity in PNAS.
by sequestering manganese, reveals the molecular mechanism of the bacterial type VI secretion system chelating manganese ions to inhibit the host's natural immune response
.
This study found that Yersinia pseudotuberculosis (Yptb) T6SS can secrete a manganese ion-binding effect protein TssS to promote the uptake of manganese ions by the bacteria
.
TssS is a small protein consisting of only 48 amino acids.
The mutant strain (ΔtssS) with the deletion of this gene is significantly less pathogenic to mice, and the bacterial load in different tissues and organs of mice infected with the ΔtssS strain is also significantly decreased
.
Transcriptomics analysis found that, compared with the wild-type strain, the expression of Type I-IFNs and IFN-stimulated genes (ISGs) in the cells infected with the ΔtssS strain was significantly increased, suggesting TssS It can inhibit the host's natural immune response; and after the manganese ion binding site in TssS is mutated, its ability to suppress the natural immune system and its pathogenicity to mice is significantly reduced, indicating that the manganese ion binding ability of TssS inhibits its innate immunity Vital
.
In mammalian cells, most manganese ions are present in different organelles
.
After viral infection, manganese ions are released into the cytoplasm to enhance the activation of cGAS-STING and the antiviral innate immune response [3]
.
This study found that LPS (gram-negative bacteria cell wall components) treatment can also significantly increase the concentration of manganese ions in the cytoplasm, but overexpression of TssS protein in cells can inhibit the activation and activation of STING induced by cGAMP/c-di-GMP.
Downstream gene expression
.
Most bacteria, including the gram-negative bacterium Yersinia pseudotuberculosis (Yptb) and the same genus Y.
pestis (Y.
pestis) and Y.
enterocolitica (Y.
enterocolitica) are produced The second messenger c-di-GMP is very important for bacterial proliferation, differentiation and infection [5]
.
Correspondingly, c-di-GMP can be recognized by STING of host cells and activate STING, triggering anti-bacterial natural immune response; and manganese ions can significantly promote their binding to STING [3, 6, 7]
.
This study further found that after wild-type Yptb or ΔtssS mutants infect wild-type mice, the bacterial load in wild-type Yptb-infected mice is significantly higher than that in ΔtssS-infected mice; and when these two strains respectively infect STING-deficient mice , The huge difference in bacterial load between different infection groups was significantly reduced
.
These results show that: on the one hand, the bacterial products LPS and c-di-GMP induce the release of manganese ions in the host cell and jointly promote the activation of STING; on the other hand, the bacteria produce and secrete TssS and chelate intracellular manganese ions to inhibit the host STING (by reducing c -di-GMP-STING combination) and the activation of downstream signaling pathways to achieve suppression of the host's natural immune response
.
Unlike other known bacterial effectors that usually cause disease by interacting with host intracellular proteins, nucleic acids and other macromolecules, this study reveals that an effector protein controls intracellular free manganese by chelating manganese ions in the host cell.
Ion concentration inhibits a new mechanism of the host’s natural immune response (as shown in the figure below)
.
As a new bacterial immune escape mechanism, this research provides a new perspective for understanding the role of T6SS in the pathogenic mechanism of bacteria.
It is not only important for understanding the molecular mechanism of pathogenic microorganisms regulating host immune response, but also for treatment.
Some diseases caused by over-activation of the autoimmune system provide new ideas
.
More importantly, similar Mn2+ binding proteins with unknown functions have been identified in the T6SS gene clusters of a large number of different species of bacteria, suggesting that the natural immune escape mechanism discovered in this study is a ubiquitous and ancient anti-host reaction mechanism in bacteria.
.
TssS chelates manganese ions to inhibit STING-mediated antibacterial innate immune response in host cells.
Zhu Lingfang, postdoctoral fellow at Northwest A&F University, Xu Lei, a young teacher, and Wang Chenguang, a postdoctoral fellow at Peking University, are the co-first authors of this paper.
Shen Xihui, Jiang Zhengfan and Zhou Dongsheng are the co-first authors of this paper.
Co-corresponding author
.
Original link: https:// Plate maker: 11 References 1.
Russell AB, Peterson SB, & Mougous JD (2014) Type VI secretion system effectors: poisons with a purpose.
Nat.
Rev.
Microbiol.
12(2): 137-148.
2.
Joshi A, et al.
(2017) Rules of engagement: the type VI secretion system in Vibrio cholerae.
Trends Microbiol.
25(4): 267-279.
3 .
Wang C, et al.
(2018) Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses.
Immunity 48(4): 675-687 e677.
4.
Si M, et al.
(2017) Manganese scavenging and oxidative stress response mediated by type VI secretion system in Burkholderia thailandensis.
Proc.
Natl.
Acad.
Sci.
USA.
114 (11): E2233-E2242.
5.
Bobrov AG, Kirillina O , &Perry RD (2005) The phosphodiesterase activity of the HmsP EAL domain is required for negative regulation of biofilm formation in Yersinia pestis.
FEMS Microbiol Lett 247(2): 123-130.
6.
Roembke BT, et al.
(2014) A cyclic dinucleotide containing 2-aminopurine is a general fluorescent sensor for c-di-GMP and 3',3'-cGAMP.
Mol Biosyst 10(6): 1568-1575.
7.
Stelitano V, et al.
(2013) Probing the activity of diguanylate cyclases and c-di-GMP phosphodiesterases in real-time by CD spectroscopy.
Nucleic Acids Res 41(7): e79.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting without permission is prohibited, the author Have all statutory rights, offenders must be investigatedStelitano V, et al.
(2013) Probing the activity of diguanylate cyclases and c-di-GMP phosphodiesterases in real-time by CD spectroscopy.
Nucleic Acids Res 41(7): e79.
Notes for reprinting [Non-original article] The copyright of this article belongs to The article is owned by the author, personal reposting and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, offenders must be investigatedStelitano V, et al.
(2013) Probing the activity of diguanylate cyclases and c-di-GMP phosphodiesterases in real-time by CD spectroscopy.
Nucleic Acids Res 41(7): e79.
Notes for reprinting [Non-original article] The copyright of this article belongs to The article is owned by the author, personal reposting and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, offenders must be investigated
.
.
As a widely distributed secretion system with complex structure, T6SS can deliver different types of effector proteins to the extracellular environment, other bacteria or host cells, so as to resist environmental stress, competition between bacteria and interaction with the host.
Play an important role [1, 2]
.
Innate immunity is the host's first line of defense against the invasion of pathogenic microorganisms.
The cGAS-STING signaling pathway plays an important role in the host's fight against a variety of viral and bacterial infections
.
In 2018, Professor Jiang Zhengfan’s laboratory revealed that manganese ions play an important role in cellular antiviral natural immunity by activating cGAS-STING [3]
.
Previous research by Professor Shen Xihui’s laboratory found that Burkholderia thailandensis T6SS mediates the transport of manganese ions by secreting a manganese ion-binding effector protein TseM, thereby promoting the anti-oxidative stress and pathogenicity of the bacteria.
【4】
.
These findings prompted them to further explore whether this type of T6SS effector protein with manganese ion binding function can regulate the host's natural immunity by affecting the manganese ion level in the host cell
.
On October 4, 2021, the laboratory of Professor Xihui Shen of Northwest A&F University cooperated with the laboratory of Professor Jiang Zhengfan of the Beijing University of Science and Technology and the laboratory of Researcher Zhou Dongsheng of the Academy of Military Medical Sciences to publish the paper T6SS translocates a micropeptide to suppress STING-mediated innate immunity in PNAS.
by sequestering manganese, reveals the molecular mechanism of the bacterial type VI secretion system chelating manganese ions to inhibit the host's natural immune response
.
This study found that Yersinia pseudotuberculosis (Yptb) T6SS can secrete a manganese ion-binding effect protein TssS to promote the uptake of manganese ions by the bacteria
.
TssS is a small protein consisting of only 48 amino acids.
The mutant strain (ΔtssS) with the deletion of this gene is significantly less pathogenic to mice, and the bacterial load in different tissues and organs of mice infected with the ΔtssS strain is also significantly decreased
.
Transcriptomics analysis found that, compared with the wild-type strain, the expression of Type I-IFNs and IFN-stimulated genes (ISGs) in the cells infected with the ΔtssS strain was significantly increased, suggesting TssS It can inhibit the host's natural immune response; and after the manganese ion binding site in TssS is mutated, its ability to suppress the natural immune system and its pathogenicity to mice is significantly reduced, indicating that the manganese ion binding ability of TssS inhibits its innate immunity Vital
.
In mammalian cells, most manganese ions are present in different organelles
.
After viral infection, manganese ions are released into the cytoplasm to enhance the activation of cGAS-STING and the antiviral innate immune response [3]
.
This study found that LPS (gram-negative bacteria cell wall components) treatment can also significantly increase the concentration of manganese ions in the cytoplasm, but overexpression of TssS protein in cells can inhibit the activation and activation of STING induced by cGAMP/c-di-GMP.
Downstream gene expression
.
Most bacteria, including the gram-negative bacterium Yersinia pseudotuberculosis (Yptb) and the same genus Y.
pestis (Y.
pestis) and Y.
enterocolitica (Y.
enterocolitica) are produced The second messenger c-di-GMP is very important for bacterial proliferation, differentiation and infection [5]
.
Correspondingly, c-di-GMP can be recognized by STING of host cells and activate STING, triggering anti-bacterial natural immune response; and manganese ions can significantly promote their binding to STING [3, 6, 7]
.
This study further found that after wild-type Yptb or ΔtssS mutants infect wild-type mice, the bacterial load in wild-type Yptb-infected mice is significantly higher than that in ΔtssS-infected mice; and when these two strains respectively infect STING-deficient mice , The huge difference in bacterial load between different infection groups was significantly reduced
.
These results show that: on the one hand, the bacterial products LPS and c-di-GMP induce the release of manganese ions in the host cell and jointly promote the activation of STING; on the other hand, the bacteria produce and secrete TssS and chelate intracellular manganese ions to inhibit the host STING (by reducing c -di-GMP-STING combination) and the activation of downstream signaling pathways to achieve suppression of the host's natural immune response
.
Unlike other known bacterial effectors that usually cause disease by interacting with host intracellular proteins, nucleic acids and other macromolecules, this study reveals that an effector protein controls intracellular free manganese by chelating manganese ions in the host cell.
Ion concentration inhibits a new mechanism of the host’s natural immune response (as shown in the figure below)
.
As a new bacterial immune escape mechanism, this research provides a new perspective for understanding the role of T6SS in the pathogenic mechanism of bacteria.
It is not only important for understanding the molecular mechanism of pathogenic microorganisms regulating host immune response, but also for treatment.
Some diseases caused by over-activation of the autoimmune system provide new ideas
.
More importantly, similar Mn2+ binding proteins with unknown functions have been identified in the T6SS gene clusters of a large number of different species of bacteria, suggesting that the natural immune escape mechanism discovered in this study is a ubiquitous and ancient anti-host reaction mechanism in bacteria.
.
TssS chelates manganese ions to inhibit STING-mediated antibacterial innate immune response in host cells.
Zhu Lingfang, postdoctoral fellow at Northwest A&F University, Xu Lei, a young teacher, and Wang Chenguang, a postdoctoral fellow at Peking University, are the co-first authors of this paper.
Shen Xihui, Jiang Zhengfan and Zhou Dongsheng are the co-first authors of this paper.
Co-corresponding author
.
Original link: https:// Plate maker: 11 References 1.
Russell AB, Peterson SB, & Mougous JD (2014) Type VI secretion system effectors: poisons with a purpose.
Nat.
Rev.
Microbiol.
12(2): 137-148.
2.
Joshi A, et al.
(2017) Rules of engagement: the type VI secretion system in Vibrio cholerae.
Trends Microbiol.
25(4): 267-279.
3 .
Wang C, et al.
(2018) Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses.
Immunity 48(4): 675-687 e677.
4.
Si M, et al.
(2017) Manganese scavenging and oxidative stress response mediated by type VI secretion system in Burkholderia thailandensis.
Proc.
Natl.
Acad.
Sci.
USA.
114 (11): E2233-E2242.
5.
Bobrov AG, Kirillina O , &Perry RD (2005) The phosphodiesterase activity of the HmsP EAL domain is required for negative regulation of biofilm formation in Yersinia pestis.
FEMS Microbiol Lett 247(2): 123-130.
6.
Roembke BT, et al.
(2014) A cyclic dinucleotide containing 2-aminopurine is a general fluorescent sensor for c-di-GMP and 3',3'-cGAMP.
Mol Biosyst 10(6): 1568-1575.
7.
Stelitano V, et al.
(2013) Probing the activity of diguanylate cyclases and c-di-GMP phosphodiesterases in real-time by CD spectroscopy.
Nucleic Acids Res 41(7): e79.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting without permission is prohibited, the author Have all statutory rights, offenders must be investigatedStelitano V, et al.
(2013) Probing the activity of diguanylate cyclases and c-di-GMP phosphodiesterases in real-time by CD spectroscopy.
Nucleic Acids Res 41(7): e79.
Notes for reprinting [Non-original article] The copyright of this article belongs to The article is owned by the author, personal reposting and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, offenders must be investigatedStelitano V, et al.
(2013) Probing the activity of diguanylate cyclases and c-di-GMP phosphodiesterases in real-time by CD spectroscopy.
Nucleic Acids Res 41(7): e79.
Notes for reprinting [Non-original article] The copyright of this article belongs to The article is owned by the author, personal reposting and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, offenders must be investigated
.
