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Life science On May 19, 2022, the team of Han Wenyuan from Huazhong Agricultural University published the research results of analyzing the immune function of the new prokaryotic Argonaute (Ago) system in the form of Article in the journal Cell Host & Micro.
The result paper is titled "A short prokaryotic Argonaute activates membrane effector to confer antiviral defense", and reports that an archaeal Ago activates transmembrane toxicity effector proteins after recognizing viral invasion, killing infected cells by triggering cell membrane depolarizati.
cells, thereby inhibiting viral proliferation and providing immune protection to the cell populati.
This immunization strategy, known as abortive infection, is employed by a variety of immune syste.
▲Long press the picture to identify the QR code to read the original text The struggle and co-evolution between microorganisms and the viruses that invaded them have lasted for billions of yea.
This struggle has forced microbes to evolve multiple immune systems to defend against virus invasi.
For example, the well-known CRISPR-Cas system recognizes and degrades viral DNA under the mediation of small RNAs, thereby providing immune protection, and Ago has a similar functi.
Interestingly, Ago is a class of immune proteins shared by eukaryotes and prokaryot.
Eukaryotic Ago binds a small piece of RNA as a guide, and under its guidance, it specifically recognizes and cleaves the target RNA, and participates in the functions of resisting the invasion of viruses and transposons, and regulating gene expressi.
The studied prokaryotic Ago often exerts immune function through DNA-mediated DNA cleava.
However, bioinformatics analysis predicted a class of short-form prokaryotic Ago proteins lacking nuclease activi.
This type of Ago accounts for about half of all prokaryotic Ago, but it has been lack of research for a long ti.
A conserved gene cluster encoding a short Ago protein was identified in Sulfolobus islandicus, which additionally encodes a possible transcriptional regulator (AgaR) and two proteins of unknown function (Aga1 and Aga
, indicating that they may form the immune system (SiAgo system) to work togeth.
The researchers expressed Ago, Aga1, and Aga2 in strains that did not contain the gene cluster, and then analyzed the response of the expressed strains to viral invasi.
The results show that the SiAgo system can simultaneously inhibit virus proliferation and strain growth, and the infected cells rapidly depolarize the cell membrane, which indicates that the SiAgo system resists virus invasion by mediating abortive infecti.
Through a series of genetic, biochemical and structural biology analyses, Han Wenyuan's group analyzed the functions of Ago, Aga1 and Aga2 (Figure
Ago and Aga1 form a stable binary complex and have the ability to specifically recognize complementary nucleic acids mediated by nucleic acid fragmen.
Aga2 is a transmembrane protein that functions as a virulence factor and can cause cell membrane depolarization when overexpress.
Aga2 specifically binds phosphatidic acid and phosphatidylinositol phosphate, which is similar to a variety of proteins that mediate programmed cell death in animal cells, reflecting the conservation of the suicide mechanism of archaea and animal cel.
In addition, the Ago-Aga1 complex interacts directly with Aga2 and is more recruited to the cell membrane after viral invasi.
Based on the above results, the researchers proposed a working model of the SiAgo system: the Ago-Aga1 complex senses virus invasion through nucleic acid recognition, and then activates Aga2 through direct interaction to mediate cell membrane depolarization, thereby killing infected cel.
This study revealed a novel immune model: Ago proteins that have lost nuclease activity still retain the ability to specifically recognize nucleic acids, so they can sense virus invasion and then activate related effector proteins to provide immune protection through abortive infecti.
More and more evidences show that this immune mode widely exists in two types of specific nucleic acid recognition systems, Ago and CRISPR-C.
Zeng Zhifeng, a doctoral student from the School of Life Science and Technology of Huazhong Agricultural University, is the first author, and Professor Han Wenyuan is the corresponding author of the stu.
Many master and undergraduate students in the research group participated in the resear.
Pr.
She Qunxin from Shandong University, Pr.
Rachel Whitaker and .
Zhang Changyi from University of Illinois at Urbana-Champaign, USA, .
Rafael Pinilla-Redondo and .
Shiraz Shah from Copenhagen University, Denmark, .
Zhao Fen and Wang Chen from the State Key Laboratory of Crop Genetic Improvement of Huazhong Agricultural University PhD also participated in part of the research wo.
This research was supported by the National Natural Science Foundation of China, the National Key R&D Program, and the Hongshan Laboratory Fu.
FigureThe SiAgo system mediates the model of abortive infection and the function of each compone.
The author's intervi.
Cell Press specially invited Professor Han Wenyuan, the corresponding author of the paper, to conduct an exclusive interview on behalf of the team, and asked him to interpret it in deta.
CellPress: Argonaute (Ago) protein is a ubiquitous nucleic acid guide enzy.
Compared with eukaryotic Agos (eAgos), what are the characteristics of prokaryotic Agos (pAgos)? Professor Han Wenyuan: Compared with eukaryotic Agos, the biggest feature of prokaryotic Agos is its high diversity, including the diversity of conserved sites, the diversity of domain composition, the diversity of guide nucleic acid and target nucleic acid categories, and the diversity of associated proteins, e.
This diversity also indicates that the functions and mechanisms of action of prokaryotic Agos are highly diversified, which is worthy of further explorati.
Taking SiAgo in this study as an example, SiAgo lacks two N-terminal domains, and the mutation of the active site leads to the loss of nuclease activi.
Its associated proteins include a possible transcription factor and two proteins with unknown functio.
It was difficult to speculate on the function of the SiAgo system until the study was carried out, and the findings also suggest that the SiAgo system provides virus defense in a way that is completely different from any known Ago prote.
In addition, it is now generally believed that eukaryotic Agos evolved from a prokaryotic Agos with nuclease activity, that is to say, eukaryotic Agos can be regarded as a branch of prokaryotic Ag.
In fact, eukaryotes can also be regarded as a branch of archa.
CellPress: How does the Sulfolobus islandicus Ago system provide virus defense? Pr.
Wenyuan Han: The SiAgo system provides immune protection by mediating abortive infecti.
This is a strategy that provides protection at the population level by killing infected cells, preventing the virus from spreadi.
This strategy requires three steps of sensing viral invasion, activating toxic proteins, and triggering cell dea.
Interestingly, a variety of immune systems, such as retron, CBASS (Cyclic-oligonucleotide-based anti-phage signaling systems), e.
, all adopt this strategy, suggesting that abortive infection is a highly efficient immune system in the microbial-virus arms ra.
Strategy, has some kind of advantage in evoluti.
CellPress: What are the functions of the two pAgos-related proteins, Aga1 and Aga2? Professor Han Wenyuan: The current results show that Aga1 and Ago form a stable complex and help the latter to bind guide nucleic acid and target nucleic acid, and participate in sensing virus invasi.
We speculate that Aga1 complements the two missing N-terminal domains of Ago, but whether Aga1 has other functions is uncle.
Aga2 is a transmembrane toxic protein that may lead to depolarization of the cell membrane by puncturing the cell membrane or forming an ion chann.
After viral invasion, it is activated by the Ago-Aga1 complex, which acts to kill cel.
CellPress: What is the role of the interaction between the Ago-Aga1 complex and Aga2 in immune sensing? Professor Han Wenyuan: Realizing abortive infection requires transmitting the virus invasion information to the virulent effector and activating the latt.
We speculate that the direct interaction between Ago-Aga1 and Aga2 plays a role in activating AgaCellPress: How can the results of this research help reveal the function of pAgos and understand the mechanism of antiviral immunity? Professor Han Wenyuan: The complex mechanism of microbial antiviral immunity is the result of billions of years of evolution in natu.
Although research in this field has progressed rapidly in the past ten years, it is still far from revealing the full picture of microbial antiviral immuni.
Research is just one small step in these advanc.
Specifically, the contributions of this research to this field are mainly in two aspec.
First, it was confirmed that prokaryotic Agos cooperated with its associated proteins to exert immune functi.
The association proteins of prokaryotic Agos were predicted by bioinformatics analysis more than a decade ago, but direct experimental evidence of their interaction has not been found until recently, and this study demonstrates their antiviral immune function for the first time, suggesting that we can further learn from th.
Associated proteins to start mining more new Ago syste.
Interestingly, it has long been considered that only those proteins encoded in the same operon as prokaryotic Agos are associated proteins, and Ago in this study is encoded in the opposite direction of its two brothers, which means that we should remove" The limitation of the same operon" is expected to excavate more novel prokaryotic Ago syste.
Secondly, the prokaryotic Agos system was pulled into the "big family" of abortive infecti.
As mentioned earlier, abortive infection is a strategy employed by multiple immune syste.
What are the advantages of this strategy? What are the reasons and mechanisms for the convergent evolution of different immune systems? This will be the focus of further research in this fie.
The author team of the paper introduces Professor Han Wenyu.
The corresponding author of the paper, Professor Han Wenyuan, obtained a master's degree and a doctorate degree from Shandong University and Copenhagen University, Denmark, and joined Huazhong Agricultural University in 201Main research directions: 1) Antiviral immune mechanism of microorganisms; 2) Application and optimization of CRISPR-Cas technolo.
He has published a number of research papers in journals such as Cell Host & Microbe, Cell Reports, Nucleic Acids Research as the correspondent and the first auth.
The first author of Zeng Zhifeng's doctoral thesis, Zeng Zhifeng, graduated from the School of Life Science and Technology of Huazhong Agricultural University with a bachelor's degr.
In 2019, Baoyan joined Han Wenyuan's research group (joint master and doctoral program), mainly dedicated to the excavation and identification of new prokaryotic Ago syste.
Chen Yu The second author of the master's thesis, Chen Yu, graduated from the School of Life Science and Technology of Huazhong Agricultural University with a bachelor's degr.
In 2020, he joined Han Wenyuan's research group and is committed to the research on the interaction between Sulfolobus and virus.
Related paper information The original paper was published on Cell Host & Microbe, a journal of CellPress Cell Pre.
The result paper is titled "A short prokaryotic Argonaute activates membrane effector to confer antiviral defense", and reports that an archaeal Ago activates transmembrane toxicity effector proteins after recognizing viral invasion, killing infected cells by triggering cell membrane depolarizati.
cells, thereby inhibiting viral proliferation and providing immune protection to the cell populati.
This immunization strategy, known as abortive infection, is employed by a variety of immune syste.
▲Long press the picture to identify the QR code to read the original text The struggle and co-evolution between microorganisms and the viruses that invaded them have lasted for billions of yea.
This struggle has forced microbes to evolve multiple immune systems to defend against virus invasi.
For example, the well-known CRISPR-Cas system recognizes and degrades viral DNA under the mediation of small RNAs, thereby providing immune protection, and Ago has a similar functi.
Interestingly, Ago is a class of immune proteins shared by eukaryotes and prokaryot.
Eukaryotic Ago binds a small piece of RNA as a guide, and under its guidance, it specifically recognizes and cleaves the target RNA, and participates in the functions of resisting the invasion of viruses and transposons, and regulating gene expressi.
The studied prokaryotic Ago often exerts immune function through DNA-mediated DNA cleava.
However, bioinformatics analysis predicted a class of short-form prokaryotic Ago proteins lacking nuclease activi.
This type of Ago accounts for about half of all prokaryotic Ago, but it has been lack of research for a long ti.
A conserved gene cluster encoding a short Ago protein was identified in Sulfolobus islandicus, which additionally encodes a possible transcriptional regulator (AgaR) and two proteins of unknown function (Aga1 and Aga
, indicating that they may form the immune system (SiAgo system) to work togeth.
The researchers expressed Ago, Aga1, and Aga2 in strains that did not contain the gene cluster, and then analyzed the response of the expressed strains to viral invasi.
The results show that the SiAgo system can simultaneously inhibit virus proliferation and strain growth, and the infected cells rapidly depolarize the cell membrane, which indicates that the SiAgo system resists virus invasion by mediating abortive infecti.
Through a series of genetic, biochemical and structural biology analyses, Han Wenyuan's group analyzed the functions of Ago, Aga1 and Aga2 (Figure
Ago and Aga1 form a stable binary complex and have the ability to specifically recognize complementary nucleic acids mediated by nucleic acid fragmen.
Aga2 is a transmembrane protein that functions as a virulence factor and can cause cell membrane depolarization when overexpress.
Aga2 specifically binds phosphatidic acid and phosphatidylinositol phosphate, which is similar to a variety of proteins that mediate programmed cell death in animal cells, reflecting the conservation of the suicide mechanism of archaea and animal cel.
In addition, the Ago-Aga1 complex interacts directly with Aga2 and is more recruited to the cell membrane after viral invasi.
Based on the above results, the researchers proposed a working model of the SiAgo system: the Ago-Aga1 complex senses virus invasion through nucleic acid recognition, and then activates Aga2 through direct interaction to mediate cell membrane depolarization, thereby killing infected cel.
This study revealed a novel immune model: Ago proteins that have lost nuclease activity still retain the ability to specifically recognize nucleic acids, so they can sense virus invasion and then activate related effector proteins to provide immune protection through abortive infecti.
More and more evidences show that this immune mode widely exists in two types of specific nucleic acid recognition systems, Ago and CRISPR-C.
Zeng Zhifeng, a doctoral student from the School of Life Science and Technology of Huazhong Agricultural University, is the first author, and Professor Han Wenyuan is the corresponding author of the stu.
Many master and undergraduate students in the research group participated in the resear.
Pr.
She Qunxin from Shandong University, Pr.
Rachel Whitaker and .
Zhang Changyi from University of Illinois at Urbana-Champaign, USA, .
Rafael Pinilla-Redondo and .
Shiraz Shah from Copenhagen University, Denmark, .
Zhao Fen and Wang Chen from the State Key Laboratory of Crop Genetic Improvement of Huazhong Agricultural University PhD also participated in part of the research wo.
This research was supported by the National Natural Science Foundation of China, the National Key R&D Program, and the Hongshan Laboratory Fu.
FigureThe SiAgo system mediates the model of abortive infection and the function of each compone.
The author's intervi.
Cell Press specially invited Professor Han Wenyuan, the corresponding author of the paper, to conduct an exclusive interview on behalf of the team, and asked him to interpret it in deta.
CellPress: Argonaute (Ago) protein is a ubiquitous nucleic acid guide enzy.
Compared with eukaryotic Agos (eAgos), what are the characteristics of prokaryotic Agos (pAgos)? Professor Han Wenyuan: Compared with eukaryotic Agos, the biggest feature of prokaryotic Agos is its high diversity, including the diversity of conserved sites, the diversity of domain composition, the diversity of guide nucleic acid and target nucleic acid categories, and the diversity of associated proteins, e.
This diversity also indicates that the functions and mechanisms of action of prokaryotic Agos are highly diversified, which is worthy of further explorati.
Taking SiAgo in this study as an example, SiAgo lacks two N-terminal domains, and the mutation of the active site leads to the loss of nuclease activi.
Its associated proteins include a possible transcription factor and two proteins with unknown functio.
It was difficult to speculate on the function of the SiAgo system until the study was carried out, and the findings also suggest that the SiAgo system provides virus defense in a way that is completely different from any known Ago prote.
In addition, it is now generally believed that eukaryotic Agos evolved from a prokaryotic Agos with nuclease activity, that is to say, eukaryotic Agos can be regarded as a branch of prokaryotic Ag.
In fact, eukaryotes can also be regarded as a branch of archa.
CellPress: How does the Sulfolobus islandicus Ago system provide virus defense? Pr.
Wenyuan Han: The SiAgo system provides immune protection by mediating abortive infecti.
This is a strategy that provides protection at the population level by killing infected cells, preventing the virus from spreadi.
This strategy requires three steps of sensing viral invasion, activating toxic proteins, and triggering cell dea.
Interestingly, a variety of immune systems, such as retron, CBASS (Cyclic-oligonucleotide-based anti-phage signaling systems), e.
, all adopt this strategy, suggesting that abortive infection is a highly efficient immune system in the microbial-virus arms ra.
Strategy, has some kind of advantage in evoluti.
CellPress: What are the functions of the two pAgos-related proteins, Aga1 and Aga2? Professor Han Wenyuan: The current results show that Aga1 and Ago form a stable complex and help the latter to bind guide nucleic acid and target nucleic acid, and participate in sensing virus invasi.
We speculate that Aga1 complements the two missing N-terminal domains of Ago, but whether Aga1 has other functions is uncle.
Aga2 is a transmembrane toxic protein that may lead to depolarization of the cell membrane by puncturing the cell membrane or forming an ion chann.
After viral invasion, it is activated by the Ago-Aga1 complex, which acts to kill cel.
CellPress: What is the role of the interaction between the Ago-Aga1 complex and Aga2 in immune sensing? Professor Han Wenyuan: Realizing abortive infection requires transmitting the virus invasion information to the virulent effector and activating the latt.
We speculate that the direct interaction between Ago-Aga1 and Aga2 plays a role in activating AgaCellPress: How can the results of this research help reveal the function of pAgos and understand the mechanism of antiviral immunity? Professor Han Wenyuan: The complex mechanism of microbial antiviral immunity is the result of billions of years of evolution in natu.
Although research in this field has progressed rapidly in the past ten years, it is still far from revealing the full picture of microbial antiviral immuni.
Research is just one small step in these advanc.
Specifically, the contributions of this research to this field are mainly in two aspec.
First, it was confirmed that prokaryotic Agos cooperated with its associated proteins to exert immune functi.
The association proteins of prokaryotic Agos were predicted by bioinformatics analysis more than a decade ago, but direct experimental evidence of their interaction has not been found until recently, and this study demonstrates their antiviral immune function for the first time, suggesting that we can further learn from th.
Associated proteins to start mining more new Ago syste.
Interestingly, it has long been considered that only those proteins encoded in the same operon as prokaryotic Agos are associated proteins, and Ago in this study is encoded in the opposite direction of its two brothers, which means that we should remove" The limitation of the same operon" is expected to excavate more novel prokaryotic Ago syste.
Secondly, the prokaryotic Agos system was pulled into the "big family" of abortive infecti.
As mentioned earlier, abortive infection is a strategy employed by multiple immune syste.
What are the advantages of this strategy? What are the reasons and mechanisms for the convergent evolution of different immune systems? This will be the focus of further research in this fie.
The author team of the paper introduces Professor Han Wenyu.
The corresponding author of the paper, Professor Han Wenyuan, obtained a master's degree and a doctorate degree from Shandong University and Copenhagen University, Denmark, and joined Huazhong Agricultural University in 201Main research directions: 1) Antiviral immune mechanism of microorganisms; 2) Application and optimization of CRISPR-Cas technolo.
He has published a number of research papers in journals such as Cell Host & Microbe, Cell Reports, Nucleic Acids Research as the correspondent and the first auth.
The first author of Zeng Zhifeng's doctoral thesis, Zeng Zhifeng, graduated from the School of Life Science and Technology of Huazhong Agricultural University with a bachelor's degr.
In 2019, Baoyan joined Han Wenyuan's research group (joint master and doctoral program), mainly dedicated to the excavation and identification of new prokaryotic Ago syste.
Chen Yu The second author of the master's thesis, Chen Yu, graduated from the School of Life Science and Technology of Huazhong Agricultural University with a bachelor's degr.
In 2020, he joined Han Wenyuan's research group and is committed to the research on the interaction between Sulfolobus and virus.
Related paper information The original paper was published on Cell Host & Microbe, a journal of CellPress Cell Pre.
