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Written by | My best friend "
cGMP-AMP-STING" D'CGMP-AMP-STING The DNA induction pathway is a core pathway of the innate immune response, plays a crucial role in antiviral immunity [1], and is also involved in autoimmune diseases [2] and anti-tumor immunity [3].
cGMP-AMP synthetase (cGAS) is an important class of nucleotide transferases that can bind to double-stranded DNA to catalyze cGMP-AMP synthesis [4].
cGAMP is a diffusible cyclic dinucleotide (CDN) that activates STING located in the endoplasmic reticulum [5].
The activated STING acts as a backbone to recruit and activate TBK1 and IRF3 sequentially, thereby inducing a type I interferon-mediated antiviral immune response [6].
The cGAS-mediated cGAMP synthesis pathway can be traced back to prokaryotes
.
Like the second messenger of all nucleotides, cGAMP cannot actively enter and leave cells
.
Among metazoans, the only enzyme known to degrade cGAMP is ENPP1, an extracellular phosphodiesterase that hydrolyzes cGAMP to GMP and AMP
.
There are two pathways for cGAMP to avoid degradation, one is the movement to the gap junction of the cell, and the other is the assembly package
.
Of course, tumor cells can release soluble cGAMP
extracellularly.
The way extracellular cGAMP enters the cell is usually through the transmembrane transport of molecules
.
Recent work has also defined extracellular cGAMP as an "immunotransmitter" involved in STING-related immune responses [7].
The idea behind this definition is that cells that produce and respond to cGAMP tend to be different
.
So, a fundamental question is, how does cGAMP leave the cell that produces it? One possible cause is that cGAMP is actively released from the disrupted cell membrane along with cell death; Another possible reason is the maturation mechanism
for transporting cGAMP within the cell.
Of course, this mechanism remains inconclusive
.
Recently, Daniel B.
Stetson's research group from the University of Washington published a report on Immunity titled ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP In the paper, it was found that ATP-binding transporter ABCC1 is an important factor
in transporting cGAMP out of the cell.
Intracellular DNA signaling can simultaneously activate two pathways, one is the cGAS-cGAMP-STING signaling pathway mentioned above, initiating an IFN-mediated antiviral response; One is activation of AIM2 inflammosomes and their downstream acute, inflammatory cell death
.
First, the authors investigated changes in cGAMP transport in the absence of AIM2
inflammasomes.
The authors determined from mice missing 13 groups of AIM2-like receptors that cGAMP delivery outside the cell does not require activation of STING signaling, and also found that viable cells can transport soluble cGAMP outside the cell, and the transport efficiency can vary by up to 60 times by cell type
.
Next, the authors focused on relevant transmembrane transporters
.
There are two main types of transmembrane transport mechanisms, one is active transport relying on electrochemical gradient, and the other is relying on ATP hydrolysis energy transmembrane transport
.
The authors put the focus of their research on the second category
.
By screening a variety of ATP-binding transporter-specific inhibitors, the authors found that the ABCC1-specific inhibitor MK-571 can effectively inhibit cGAMP transport out of the cell, resulting in intracellular cGAMP accumulation, which is dose-dependent in mouse and human
cultured cells.
The authors further confirmed that cGAMP in cells lacking ABCC1 was also not efficiently transported out of the cell
.
ABCC1 mediates direct ATP-dependent cGAMP transport, and this mechanism is highly conserved, also in
arthropods and chordates.
Finally, the authors study the relationship
between the above mechanism and the STING signaling pathway.
The authors found that regulating the expression level of ABCC1 can alter DNA-driven antiviral responses, so ABCC1 can also be defined as an endogenous inhibitor of the STING signaling pathway, and mutations in the gene encoding the human TREX1 DNA exonuclease can lead to a rare and severe class of autoimmune diseases known as Aicardi-Goutie'res Syndrome
。 Previous work by the authors pointed out that TREX1 is one of the important negative regulators of
the cGAS-STING signaling pathway.
The authors found through an autoimmune disease model of TREX1-deficient mice that ABCC1 can also play a key role
in negatively regulating the cGAS-cGAMP-STING pathway in this in vivo chronic cGAS activation model.
Taken together, the authors determined that ABCC1 is a class of ATP-dependent transporters
that transport cGAMP out of cells outside the cell.
ABCC1 deletion can inhibit cGAMP extracellular transport and promote the STING signaling pathway
.
In TREX1-deficient mouse autoimmune disease models, ABCC1 can inhibit the cGAS pathway
.
Platemaker: Eleven
1.
Goubau, D.
, Deddouche, S.
, and Reis e Sousa, C.
(2013).
Cytosolic sensing of viruses.
Immunity 38, 855–869.
2.
Crowl, J.
T.
, Gray, E.
E.
, Pestal, K.
, Volkman, H.
E.
, and Stetson, D.
B.
(2017).
Intracellular Nucleic Acid Detection in Autoimmunity.
Annu.
Rev.
Immunol.
35, 313–3363.
Li, T.
, and Chen, Z.
J.
(2018).
The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer.
J.
Exp.
Med.
215, 1287–1299.
4.
Sun, L.
, Wu, J.
, Du, F.
, Chen, X.
, and Chen, Z.
J.
(2013).
Cyclic GMP-AMP syn- thase is a cytosolic DNA sensor that activates the type I interferon pathway.
Science 339, 786–791.
5.
Ishikawa, H.
, Ma, Z.
, and Barber, G.
N.
(2009).
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
Nature 461, 788–792.
6.
Liu, S.
, Cai, X.
, Wu, J.
, Cong, Q.
, Chen, X.
, Li, T.
, Du, F.
, Ren, J.
, Wu, Y.
T.
, Grishin, N.
V.
, and Chen, Z.
J.
(2015).
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation.
Science 347, aaa2630.
7.
Ritchie, C.
, Carozza, J.
A.
, and Li, L.
(2022).
Biochemistry, cell biology, and pathophysiology of the innate immune cGAS-cGAMP-STING pathway.
Annu.
Rev.
Biochem.
91, 599–628.
cGMP-AMP-STING" D'CGMP-AMP-STING The DNA induction pathway is a core pathway of the innate immune response, plays a crucial role in antiviral immunity [1], and is also involved in autoimmune diseases [2] and anti-tumor immunity [3].
cGMP-AMP synthetase (cGAS) is an important class of nucleotide transferases that can bind to double-stranded DNA to catalyze cGMP-AMP synthesis [4].
cGAMP is a diffusible cyclic dinucleotide (CDN) that activates STING located in the endoplasmic reticulum [5].
The activated STING acts as a backbone to recruit and activate TBK1 and IRF3 sequentially, thereby inducing a type I interferon-mediated antiviral immune response [6].
The cGAS-mediated cGAMP synthesis pathway can be traced back to prokaryotes
.
Like the second messenger of all nucleotides, cGAMP cannot actively enter and leave cells
.
Among metazoans, the only enzyme known to degrade cGAMP is ENPP1, an extracellular phosphodiesterase that hydrolyzes cGAMP to GMP and AMP
.
There are two pathways for cGAMP to avoid degradation, one is the movement to the gap junction of the cell, and the other is the assembly package
.
Of course, tumor cells can release soluble cGAMP
extracellularly.
The way extracellular cGAMP enters the cell is usually through the transmembrane transport of molecules
.
Recent work has also defined extracellular cGAMP as an "immunotransmitter" involved in STING-related immune responses [7].
The idea behind this definition is that cells that produce and respond to cGAMP tend to be different
.
So, a fundamental question is, how does cGAMP leave the cell that produces it? One possible cause is that cGAMP is actively released from the disrupted cell membrane along with cell death; Another possible reason is the maturation mechanism
for transporting cGAMP within the cell.
Of course, this mechanism remains inconclusive
.
Recently, Daniel B.
Stetson's research group from the University of Washington published a report on Immunity titled ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP In the paper, it was found that ATP-binding transporter ABCC1 is an important factor
in transporting cGAMP out of the cell.
Intracellular DNA signaling can simultaneously activate two pathways, one is the cGAS-cGAMP-STING signaling pathway mentioned above, initiating an IFN-mediated antiviral response; One is activation of AIM2 inflammosomes and their downstream acute, inflammatory cell death
.
First, the authors investigated changes in cGAMP transport in the absence of AIM2
inflammasomes.
The authors determined from mice missing 13 groups of AIM2-like receptors that cGAMP delivery outside the cell does not require activation of STING signaling, and also found that viable cells can transport soluble cGAMP outside the cell, and the transport efficiency can vary by up to 60 times by cell type
.
Next, the authors focused on relevant transmembrane transporters
.
There are two main types of transmembrane transport mechanisms, one is active transport relying on electrochemical gradient, and the other is relying on ATP hydrolysis energy transmembrane transport
.
The authors put the focus of their research on the second category
.
By screening a variety of ATP-binding transporter-specific inhibitors, the authors found that the ABCC1-specific inhibitor MK-571 can effectively inhibit cGAMP transport out of the cell, resulting in intracellular cGAMP accumulation, which is dose-dependent in mouse and human
cultured cells.
The authors further confirmed that cGAMP in cells lacking ABCC1 was also not efficiently transported out of the cell
.
ABCC1 mediates direct ATP-dependent cGAMP transport, and this mechanism is highly conserved, also in
arthropods and chordates.
Finally, the authors study the relationship
between the above mechanism and the STING signaling pathway.
The authors found that regulating the expression level of ABCC1 can alter DNA-driven antiviral responses, so ABCC1 can also be defined as an endogenous inhibitor of the STING signaling pathway, and mutations in the gene encoding the human TREX1 DNA exonuclease can lead to a rare and severe class of autoimmune diseases known as Aicardi-Goutie'res Syndrome
。 Previous work by the authors pointed out that TREX1 is one of the important negative regulators of
the cGAS-STING signaling pathway.
The authors found through an autoimmune disease model of TREX1-deficient mice that ABCC1 can also play a key role
in negatively regulating the cGAS-cGAMP-STING pathway in this in vivo chronic cGAS activation model.
Taken together, the authors determined that ABCC1 is a class of ATP-dependent transporters
that transport cGAMP out of cells outside the cell.
ABCC1 deletion can inhibit cGAMP extracellular transport and promote the STING signaling pathway
.
In TREX1-deficient mouse autoimmune disease models, ABCC1 can inhibit the cGAS pathway
.
Original link:
https://doi.
org/10.
1016/j.
immuni.
2022.
08.
006
Platemaker: Eleven
References
1.
Goubau, D.
, Deddouche, S.
, and Reis e Sousa, C.
(2013).
Cytosolic sensing of viruses.
Immunity 38, 855–869.
2.
Crowl, J.
T.
, Gray, E.
E.
, Pestal, K.
, Volkman, H.
E.
, and Stetson, D.
B.
(2017).
Intracellular Nucleic Acid Detection in Autoimmunity.
Annu.
Rev.
Immunol.
35, 313–3363.
Li, T.
, and Chen, Z.
J.
(2018).
The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer.
J.
Exp.
Med.
215, 1287–1299.
4.
Sun, L.
, Wu, J.
, Du, F.
, Chen, X.
, and Chen, Z.
J.
(2013).
Cyclic GMP-AMP syn- thase is a cytosolic DNA sensor that activates the type I interferon pathway.
Science 339, 786–791.
5.
Ishikawa, H.
, Ma, Z.
, and Barber, G.
N.
(2009).
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
Nature 461, 788–792.
6.
Liu, S.
, Cai, X.
, Wu, J.
, Cong, Q.
, Chen, X.
, Li, T.
, Du, F.
, Ren, J.
, Wu, Y.
T.
, Grishin, N.
V.
, and Chen, Z.
J.
(2015).
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation.
Science 347, aaa2630.
7.
Ritchie, C.
, Carozza, J.
A.
, and Li, L.
(2022).
Biochemistry, cell biology, and pathophysiology of the innate immune cGAS-cGAMP-STING pathway.
Annu.
Rev.
Biochem.
91, 599–628.
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