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Written | My girlfriend, old Red Riding Hood, the body’s innate immune system can sense pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharides and nucleic acids, through pattern recognition receptors (PRRs) 【1】
.
In response to the recognition and killing of the immune system, pathogens suppress the immune response by secreting virulence factors [2]
.
Subsequently, the host of the pathogen will also correspondingly evolve a type of protection mechanism to destroy the role of virulence factors [3,4].
For example, the plant's immune system can detect pathogen invasion in real time, thereby maintaining the integrity of its own immune system.
And stability
.
For mammals, a variety of immune response pathways can induce pathogen virulence factors
.
How the body protects itself from the invasion of pathogens, especially viruses, is still poorly understood
.
On November 10, 2021, the Russell E.
Vance research group from the University of California at Berkeley published an article entitled Self-guarding of MORC3 enables virulence factor-triggered immunity in Nature, focusing on how the body fights virus invasion
.
Herpes simplex virus type 1 (HSV-1) is a type of double-stranded DNA virus
.
Its genome can be recognized as a type of pathogen-related pattern molecules by the pattern recognition receptor cGAS, which initiates the transcriptional activation of interferon-related genes, which is the STING signaling pathway [5]
.
This signaling pathway can activate the downstream kinases TBK1 and IkBe, and then phosphorylate and activate the interferon regulatory factors IRF3 and IRF7, thereby inducing a series of interferon transcription and secretion
.
Next, the interferon can bind to the interferon receptor to induce the transcription of interferon-stimulated genes (ISGs) with antiviral functions
.
After HSV-1 invades the body, it will encounter a series of host attacks.
For example, IFI16 and ND10 nuclei can inhibit viral transcription [6, 7]
.
Correspondingly, HSV-1 can induce the inactivation and degradation of IFI16 and ND10 through the E3 ubiquitination ligase ICPO, thereby promoting self-replication [8]
.
In order to further study HSV-1 infection and the immune response process of the body, the author took human monocytes infected with HSV-1 as the research object and found that the transcription and secretion of interferon does not only depend on STING, TBK1–IKKε or IRF3/7 In contrast to the monocytes with double-stranded DNA introduced into the control group, the interferon transcription is completely dependent on STING, TBK1–IKKε and IRF3/7
.
In-depth research found that only when the STING signal pathway and ICP0 are missing at the same time, the production of interferon induced by HSV-1 can be completely inhibited
.
In addition, the authors found through overexpression of ICP0 in human monocytes that the expression of ICP0 can induce the production of interferon, and the induction level is extremely high (more than ten thousand times), and this process does not depend on the STING signal pathway
.
The author speculates that ICP0 is likely to induce the secretion of interferon by degrading certain types of interferon inhibitors
.
In order to confirm this hypothesis, the authors took a genome-wide CRISPR screening and found that the targeted knockout of the SUMOylated nuclear protein MORC3 by sgRNA can induce the production of interferon
.
At the same time, it has been reported that mice carrying MORC3 mutations secrete abnormally of interferon
.
Based on the above results, the author focused on the specific function of MORC3 in the process of ICP0 inducing interferon
.
MORC3 is a member of the MORC gyrase gene family and co-localizes with the ND10 nucleosome
.
The authors determined that MORC3 has dual functions, one is to inhibit virus replication, and the other is to inhibit the secretion of interferon
.
Moreover, MORC3 specifically acts on the interferon IFNB1 site, and the induction of antiviral ISG is completely dependent on IFNB1
.
Finally, the author used ATAC-seq to screen out the target factor of MORC3 in intron FOCAD and named it MORC3-regulated element (MORC3-regulated element, MRE for short), and the position of FOCAD is about 100bp downstream of IFNB1
.
In summary, the author integrated high-throughput screening and molecular biology research methods, and discovered a new body after the virus invasion, so it has an immune induction mechanism and a response mechanism, that is, the MORC3 signaling pathway can detect DNA viruses.
The virulence factor of HSV-1, such as ICP0 of HSV-1
.
In this process, MORC3 has two effects.
One is that it can inhibit the replication of HSV-1, but HSV-1 can degrade MORC3 through ICP0; the other is that it acts on the adjacent interferon gene IFNB1 in the case of virus invasion.
MORC3 regulatory element, thereby promoting the induced secretion of interferon
.
The dual role of MORC3 plays a key role in the body's defense against virus invasion
.
Original link: https://doi.
org/10.
1038/s41586-021-04054-5 Platemaker: Eleven References [1] Janeway, CA, Jr Approaching the asymptote? Evolution and revolution in immunology.
Cold Spring Harb.
Symp .
Quant.
Biol.
54, 1–13 (1989).
[2] Lopes Fischer, N.
, Naseer, N.
, Shin, S.
& Brodsky, IE Effector-triggered immunity and pathogen sensing in metazoans.
Nat.
Microbiol.
5, 14–26 (2020).
[3] Jones, JD & Dangl, JL The plant immune system.
Nature 444, 323–329 (2006).
[4] Van der Biezen, EA & Jones, JD Plant disease-resistance proteins and the gene-for-gene concept.
Trends Biochem.
Sci.
23, 454–456 (1998).
[5] Hopfner, KP & Hornung, V.
Molecular mechanisms and cellular functions of cGAS–STING signalling.
Nat.
Rev.
Mol.
Cell Biol.
21, 501–521 (2020).
[6] Scherer, M.
& Stamminger, T.
Emerging role of PML nuclear bodies in innate immune signaling.
J.
Virol.
90,5850–5854 (2016).
[7] Everett, RD, Boutell, C.
& Hale, BG Interplay between viruses and host sumoylation pathways.
Nat.
Rev.
Microbiol.
11, 400–411 (2013).
[8] Sacks, WR & Schaffer, PA Deletion mutants in the gene encoding the herpes simplex virus type 1 immediate-early protein ICP0 exhibit impaired growth in cell culture.
J.
Virol.
61, 829–839 (1987).
Instructions for reprinting 【Original Article】BioArt Original Articles, personal reposting and sharing are welcome, reprinting is prohibited without permission, the copyrights of all published works are owned by BioArtReprinting Instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArtReprinting Instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
.
In response to the recognition and killing of the immune system, pathogens suppress the immune response by secreting virulence factors [2]
.
Subsequently, the host of the pathogen will also correspondingly evolve a type of protection mechanism to destroy the role of virulence factors [3,4].
For example, the plant's immune system can detect pathogen invasion in real time, thereby maintaining the integrity of its own immune system.
And stability
.
For mammals, a variety of immune response pathways can induce pathogen virulence factors
.
How the body protects itself from the invasion of pathogens, especially viruses, is still poorly understood
.
On November 10, 2021, the Russell E.
Vance research group from the University of California at Berkeley published an article entitled Self-guarding of MORC3 enables virulence factor-triggered immunity in Nature, focusing on how the body fights virus invasion
.
Herpes simplex virus type 1 (HSV-1) is a type of double-stranded DNA virus
.
Its genome can be recognized as a type of pathogen-related pattern molecules by the pattern recognition receptor cGAS, which initiates the transcriptional activation of interferon-related genes, which is the STING signaling pathway [5]
.
This signaling pathway can activate the downstream kinases TBK1 and IkBe, and then phosphorylate and activate the interferon regulatory factors IRF3 and IRF7, thereby inducing a series of interferon transcription and secretion
.
Next, the interferon can bind to the interferon receptor to induce the transcription of interferon-stimulated genes (ISGs) with antiviral functions
.
After HSV-1 invades the body, it will encounter a series of host attacks.
For example, IFI16 and ND10 nuclei can inhibit viral transcription [6, 7]
.
Correspondingly, HSV-1 can induce the inactivation and degradation of IFI16 and ND10 through the E3 ubiquitination ligase ICPO, thereby promoting self-replication [8]
.
In order to further study HSV-1 infection and the immune response process of the body, the author took human monocytes infected with HSV-1 as the research object and found that the transcription and secretion of interferon does not only depend on STING, TBK1–IKKε or IRF3/7 In contrast to the monocytes with double-stranded DNA introduced into the control group, the interferon transcription is completely dependent on STING, TBK1–IKKε and IRF3/7
.
In-depth research found that only when the STING signal pathway and ICP0 are missing at the same time, the production of interferon induced by HSV-1 can be completely inhibited
.
In addition, the authors found through overexpression of ICP0 in human monocytes that the expression of ICP0 can induce the production of interferon, and the induction level is extremely high (more than ten thousand times), and this process does not depend on the STING signal pathway
.
The author speculates that ICP0 is likely to induce the secretion of interferon by degrading certain types of interferon inhibitors
.
In order to confirm this hypothesis, the authors took a genome-wide CRISPR screening and found that the targeted knockout of the SUMOylated nuclear protein MORC3 by sgRNA can induce the production of interferon
.
At the same time, it has been reported that mice carrying MORC3 mutations secrete abnormally of interferon
.
Based on the above results, the author focused on the specific function of MORC3 in the process of ICP0 inducing interferon
.
MORC3 is a member of the MORC gyrase gene family and co-localizes with the ND10 nucleosome
.
The authors determined that MORC3 has dual functions, one is to inhibit virus replication, and the other is to inhibit the secretion of interferon
.
Moreover, MORC3 specifically acts on the interferon IFNB1 site, and the induction of antiviral ISG is completely dependent on IFNB1
.
Finally, the author used ATAC-seq to screen out the target factor of MORC3 in intron FOCAD and named it MORC3-regulated element (MORC3-regulated element, MRE for short), and the position of FOCAD is about 100bp downstream of IFNB1
.
In summary, the author integrated high-throughput screening and molecular biology research methods, and discovered a new body after the virus invasion, so it has an immune induction mechanism and a response mechanism, that is, the MORC3 signaling pathway can detect DNA viruses.
The virulence factor of HSV-1, such as ICP0 of HSV-1
.
In this process, MORC3 has two effects.
One is that it can inhibit the replication of HSV-1, but HSV-1 can degrade MORC3 through ICP0; the other is that it acts on the adjacent interferon gene IFNB1 in the case of virus invasion.
MORC3 regulatory element, thereby promoting the induced secretion of interferon
.
The dual role of MORC3 plays a key role in the body's defense against virus invasion
.
Original link: https://doi.
org/10.
1038/s41586-021-04054-5 Platemaker: Eleven References [1] Janeway, CA, Jr Approaching the asymptote? Evolution and revolution in immunology.
Cold Spring Harb.
Symp .
Quant.
Biol.
54, 1–13 (1989).
[2] Lopes Fischer, N.
, Naseer, N.
, Shin, S.
& Brodsky, IE Effector-triggered immunity and pathogen sensing in metazoans.
Nat.
Microbiol.
5, 14–26 (2020).
[3] Jones, JD & Dangl, JL The plant immune system.
Nature 444, 323–329 (2006).
[4] Van der Biezen, EA & Jones, JD Plant disease-resistance proteins and the gene-for-gene concept.
Trends Biochem.
Sci.
23, 454–456 (1998).
[5] Hopfner, KP & Hornung, V.
Molecular mechanisms and cellular functions of cGAS–STING signalling.
Nat.
Rev.
Mol.
Cell Biol.
21, 501–521 (2020).
[6] Scherer, M.
& Stamminger, T.
Emerging role of PML nuclear bodies in innate immune signaling.
J.
Virol.
90,5850–5854 (2016).
[7] Everett, RD, Boutell, C.
& Hale, BG Interplay between viruses and host sumoylation pathways.
Nat.
Rev.
Microbiol.
11, 400–411 (2013).
[8] Sacks, WR & Schaffer, PA Deletion mutants in the gene encoding the herpes simplex virus type 1 immediate-early protein ICP0 exhibit impaired growth in cell culture.
J.
Virol.
61, 829–839 (1987).
Instructions for reprinting 【Original Article】BioArt Original Articles, personal reposting and sharing are welcome, reprinting is prohibited without permission, the copyrights of all published works are owned by BioArtReprinting Instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArtReprinting Instructions [Original Articles] BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
