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Commit 5e38fd29 authored by Remi  PLANEL's avatar Remi PLANEL
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...@@ -14,6 +14,6 @@ You'll find information on : ...@@ -14,6 +14,6 @@ You'll find information on :
3. [Triggers of defense systems](/general-concepts/defense-systems_trigger) 3. [Triggers of defense systems](/general-concepts/defense-systems_trigger)
4. [Effectors of defense systems](/general-concepts/defense-systems_effector) 4. [Effectors of defense systems](/general-concepts/defense-systems_effector)
5. [How defense systems were and are discovered](/general-concepts/defense-systems-discovery) 5. [How defense systems were and are discovered](/general-concepts/defense-systems-discovery)
6. [Defensive domains](/general-concepts/defensive-domains/) 6. [Defensive domains](/general-concepts/defensive-domains)
7. [MGE and defense systems](/general-concepts/mge-defense-systems/) 7. [MGE and defense systems](/general-concepts/mge-defense-systems)
8. [Anti defense systems](/general-concepts/anti-defense-systems/) 8. [Anti defense systems](/general-concepts/anti-defense-systems)
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...@@ -20,7 +20,15 @@ relevantAbstracts: ...@@ -20,7 +20,15 @@ relevantAbstracts:
--- ---
The term abortive infection was coined in the 1950s :ref{doi=10.1128/jb.68.1.36-42.1954} to describe the observations that a fraction of the bacterial population did not support phage replication. This phenomenon, also called phage exclusion, was identified in multiple systems across the following decades :ref{doi=10.1016/0006-3002(61)90455-3,10.1016/0022-2836(68)90078-8,10.1128/jvi.4.2.162-168.1969,10.1128/jvi.13.4.870-880.1974} and reviewed extensively :ref{doi=10.1128/mr.45.1.52-71.1981,10.3168/jds.S0022-0302(90)78904-7,10.1111/j.1365-2958.1995.tb02255.x}. In the following years, and through the resolution of molecular mechanisms of key defense systems such as Rex or Lit, abortive infection became synonymous with infection-induced controlled cell-death. Controlled cell death upon detection of the phage infection stops the propagation of the phage and protects the rest of the bacterial population :ref{doi=10.1016/S0960-9822(00)00124-X,10.1016/j.mib.2005.06.006}. Abortive infection can thus be thought of as a form of bacterial altruism. The term abortive infection was coined in the 1950s :ref{doi=10.1128/jb.68.1.36-42.1954}
to describe the observations that a fraction of the bacterial population did not support phage replication.
This phenomenon, also called phage exclusion, was identified in multiple systems across the following decades
:ref{doi=10.1016/0006-3002(61)90455-3,10.1016/0022-2836(68)90078-8,10.1128/jvi.4.2.162-168.1969,10.1128/jvi.13.4.870-880.1974}
and reviewed extensively :ref{doi=10.1128/mr.45.1.52-71.1981,10.3168/jds.S0022-0302(90)78904-7,10.1111/j.1365-2958.1995.tb02255.x}.
In the following years, and through the resolution of molecular mechanisms of key defense systems such as Rex or Lit, abortive infection became synonymous with infection-induced controlled cell-death.
Controlled cell death upon detection of the phage infection stops the propagation of the phage and protects the rest of the bacterial population
:ref{doi=10.1016/S0960-9822(00)00124-X,10.1016/j.mib.2005.06.006}.
Abortive infection can thus be thought of as a form of bacterial altruism.
With the recent developments in phage-defense systems and microbial immunity (see :ref{doi=10.1038/s41579-023-00934-x} for a review), many newly identifed anti-phage defense systems are thought to function through abortive infection. Abortive defense systems often detect the phage infection at the later stage through protein sensing or the monitoring of host integrity but can also be based on nucleic acid sensing. Upon sensing, a diverse set of effectors can be used to reduce metabolism or induce cell-death (e.g., NAD+ depletion, translation interruption or membrane depolarisation). The diversity of and mechanisms of abortive infection were recently reviewd here :ref{doi=10.1146/annurev-virology-011620-040628}, while the evolutionary success of this paradoxical altruistic form of immunity has recently been discussed here :ref{doi=10.1016/j.mib.2023.102312}. With the recent developments in phage-defense systems and microbial immunity (see :ref{doi=10.1038/s41579-023-00934-x} for a review), many newly identifed anti-phage defense systems are thought to function through abortive infection. Abortive defense systems often detect the phage infection at the later stage through protein sensing or the monitoring of host integrity but can also be based on nucleic acid sensing. Upon sensing, a diverse set of effectors can be used to reduce metabolism or induce cell-death (e.g., NAD+ depletion, translation interruption or membrane depolarisation). The diversity of and mechanisms of abortive infection were recently reviewd here :ref{doi=10.1146/annurev-virology-011620-040628}, while the evolutionary success of this paradoxical altruistic form of immunity has recently been discussed here :ref{doi=10.1016/j.mib.2023.102312}.
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...@@ -19,4 +19,5 @@ To examplify this idea, the figure is a depiction of the ThsA protein involved i ...@@ -19,4 +19,5 @@ To examplify this idea, the figure is a depiction of the ThsA protein involved i
Although a considerable diversity of molecular mechanisms have been described for defense systems, it is striking to observe that some functional domains are recurrently involved in antiphage defense :ref{doi=10.1038/s41586-021-04098-7}. When studying the presence of a new defense system, the *in silico* characterization of the domains present in the system can provide valuable information regarding the molecular mechanism of the system. If one protein of the system contains for example a TerB domain, this might indicate that the system is involved in membrane integrity surveillance as this domain was previously shown to be associated with the periplasmic membrane :ref{doi=10.1016/j.chom.2022.09.017}. If a protein of the system contains a TIR domain this might indicate that the system possess a NAD degradation activity or that the protein could multimerize as both functions have been shown for this domain in the past :ref{doi=10.3389/fimmu.2021.784484}. Although a considerable diversity of molecular mechanisms have been described for defense systems, it is striking to observe that some functional domains are recurrently involved in antiphage defense :ref{doi=10.1038/s41586-021-04098-7}. When studying the presence of a new defense system, the *in silico* characterization of the domains present in the system can provide valuable information regarding the molecular mechanism of the system. If one protein of the system contains for example a TerB domain, this might indicate that the system is involved in membrane integrity surveillance as this domain was previously shown to be associated with the periplasmic membrane :ref{doi=10.1016/j.chom.2022.09.017}. If a protein of the system contains a TIR domain this might indicate that the system possess a NAD degradation activity or that the protein could multimerize as both functions have been shown for this domain in the past :ref{doi=10.3389/fimmu.2021.784484}.
# Domains can be conserved throughout evolution # Domains can be conserved throughout evolution
It is clear that some defense systems can be conserved among different clades of bacteria but it was also observed that the unit of evolutionary conservation can be the protein domain :ref{doi=10.1038/s41467-022-30269-9}. As a consequence, it is frequent to find the same domain associated with a wide range of distinct other domains in different defense systems :ref{doi=10.1016/j.mib.2023.102312}. This is well illustrated by defense systems such [Avs](/defense-systems/avs) or [CBASS](/defense-systems/cbass) that can be constituted of diverse effector proteins which differ from each other based on the specific domains that compose them :ref{doi=10.1126/science.aba0372}, :ref{doi=10.1038/s41564-022-01239-0}, :ref{doi=10.1038/s41564-020-0777-y}. The modular aspect of protein domains fits with the concept of "evolution as tinkering" stating that already existing objects (here protein domains) can often be repurposed in new manners, allowing the efficient development of novel functions :ref{doi=10.1126/science.860134}. It is clear that some defense systems can be conserved among different clades of bacteria but it was also observed that the unit of evolutionary conservation can be the protein domain :ref{doi=10.1038/s41467-022-30269-9}. As a consequence, it is frequent to find the same domain associated with a wide range of distinct other domains in different defense systems :ref{doi=10.1016/j.mib.2023.102312}. This is well illustrated by defense systems such [Avs](/defense-systems/avs) or [CBASS](/defense-systems/cbass) that can be constituted of diverse effector proteins which differ from each other based on the specific domains that compose them :ref{doi=10.1126/science.aba0372}, :ref{doi=10.1038/s41564-022-01239-0}, :ref{doi=10.1038/s41564-020-0777-y}. The modular aspect of protein domains fits with the concept of "evolution as tinkering" stating that already existing objects (here protein domains) can often be repurposed in new manners, allowing the efficient development of novel functions :ref{doi=10.1126/science.860134}.
...@@ -9,22 +9,32 @@ contributors: ...@@ -9,22 +9,32 @@ contributors:
# Defense systems effectors # Defense systems effectors
Most of the anti-phage defense systems of bacteria can be described as a combination of two main components. First, a sensing component that detects phage infection to trigger the immune response (see [defense-systems_trigger](/general-concepts/defense-systems_trigger/)). Second, an effector component that mediates the immune response following the detection of phage infection. Most of the anti-phage defense systems of bacteria can be described as a combination of two main components.
First, a sensing component that detects phage infection to trigger the immune response
(see [defense-systems_trigger](/general-concepts/defense-systems_trigger/)).
Second, an effector component that mediates the immune response following the detection of phage infection.
The effector components of anti-phage systems are very diverse, and can be arbitrarily distributed in broad categories :ref{doi=10.1038/s41579-023-00934-x} : The effector components of anti-phage systems are very diverse, and can be arbitrarily distributed in broad categories :ref{doi=10.1038/s41579-023-00934-x} :
## Nucleic-acid-degrading effectors. ## Nucleic-acid-degrading effectors.
Many defense systems target (either through cleavage or modification) nucleic acids to mediate the immune response. These nucleic acids targeting systems are divided between systems that specifically target phage nucleic acids to stop phage replication, and systems that untargetedly affect bacterial and viral nucleic acids to halt the growth of both the infected host and the phage. Many defense systems target (either through cleavage or modification) nucleic acids to mediate the immune response.
These nucleic acids targeting systems are divided between systems that specifically target phage nucleic acids to stop
phage replication, and systems that untargetedly affect bacterial and viral nucleic acids to halt the growth of both the
infected host and the phage.
Nucleic-acid-degrading systems include [RM](/defense-systems/rm), [CRISPR-Cas](/defense-systems/cas), [Ssp](/defense-systems/sspbcde) and [Ddn](/defense-systems/dnd), certain types of [CBASS](/defense-systems/cbass), [Avs](/defense-systems/avs) and [Lamassu](/defense-systems/lamassu-fam), [PrrC](/defense-systems/prrc), [RloC](/defense-systems/rloc)... Nucleic-acid-degrading systems include [RM](/defense-systems/rm), [CRISPR-Cas](/defense-systems/cas), [Ssp](/defense-systems/sspbcde) and [Ddn](/defense-systems/dnd), certain types of [CBASS](/defense-systems/cbass), [Avs](/defense-systems/avs) and [Lamassu](/defense-systems/lamassu-fam), [PrrC](/defense-systems/prrc), [RloC](/defense-systems/rloc)...
## Nucleotide-modifying effectors. ## Nucleotide-modifying effectors.
Other types of defense systems target the nucleotide pool of the infected cell. For instance, Viperins produce modified nucleotides that inhibit phage transcription; defensive dCTP deaminases and dGTPases respectively degrade CTP and GTP to halt phage infection; [Thoeris](/defense-systems/thoeris), [DSR](/defense-systems/dsr) and certain types of [pAgo](/defense-systems/pago) and [CBASS](/defense-systems/cbass) degrade NAD+ to cause growth arrest of the infected host. Other types of defense systems target the nucleotide pool of the infected cell.
For instance, Viperins produce modified nucleotides that inhibit phage transcription; defensive dCTP deaminases and dGTPases respectively
degrade CTP and GTP to halt phage infection; [Thoeris](/defense-systems/thoeris), [DSR](/defense-systems/dsr) and certain types of [pAgo](/defense-systems/pago) and [CBASS](/defense-systems/cbass) degrade NAD+ to cause growth arrest of the infected host.
## Membrane-disrupting effectors. ## Membrane-disrupting effectors.
Many defense systems encode proteins that disrupt the membrane integrity of the infected cell (by opening pores, targeting the membrane phospholipids or through transmembrane domains), leading to growth arrest. They include for instance bacterial Gasdermins, RexAB, Pif, AbiZ, certain types of [pAgo](/defense-systems/pago), [retrons](/defense-systems/retron), [CBASS](/defense-systems/cbass), [PYCSAR](/defense-systems/pycsar) and [Avs](/defense-systems/avs) systems. Many defense systems encode proteins that disrupt the membrane integrity of the infected cell
(by opening pores, targeting the membrane phospholipids or through transmembrane domains), leading to growth arrest.
They include for instance bacterial Gasdermins, RexAB, Pif, AbiZ, certain types of [pAgo](/defense-systems/pago), [retrons](/defense-systems/retron), [CBASS](/defense-systems/cbass), [PYCSAR](/defense-systems/pycsar) and [Avs](/defense-systems/avs) systems.
## Other types of effectors. ## Other types of effectors.
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...@@ -41,7 +41,7 @@ Akin to long-A pAgogs, long B-pAgos have a N-L1-PAZ-L2-MID-PIWI domain compositi ...@@ -41,7 +41,7 @@ Akin to long-A pAgogs, long B-pAgos have a N-L1-PAZ-L2-MID-PIWI domain compositi
### Short pAgos ### Short pAgos
Short pAgos are truncated: they only contain the MID and PIWI domains essential for guide-mediate target binding :ref{doi=10.1016/j.tcb.2022.10.005}. They are catalytically inactive and are co-encoded with an APAZ domain that is fused to one of various effector domains. In short pAgo systems characterized to date, the short pAgo and the APAZ domain-containing protein form a heterodimeric complex :ref{doi=10.1016/j.cell.2022.03.012,10.1038/s41564-022-01239-0}. Within this complex, the short pAgo uses a guide RNA to bind complementary target DNAs. This triggers catalytic activation of the effector domain fused to the APAZ domain, generally resulting in cell death :ref{doi=10.1016/j.cell.2022.03.012,10.1038/s41564-022-01239-0}. As such, short pAgo systems mediate abortive infection. Short pAgos are truncated: they only contain the MID and PIWI domains essential for guide-mediate target binding :ref{doi=10.1016/j.tcb.2022.10.005}. They are catalytically inactive and are co-encoded with an APAZ domain that is fused to one of various effector domains. In short pAgo systems characterized to date, the short pAgo and the APAZ domain-containing protein form a heterodimeric complex :ref{doi=10.1016/j.cell.2022.03.012,10.1038/s41564-022-01239-0}. Within this complex, the short pAgo uses a guide RNA to bind complementary target DNAs. This triggers catalytic activation of the effector domain fused to the APAZ domain, generally resulting in cell death :ref{doi=10.1016/j.cell.2022.03.012,10.1038/s41564-022-01239-0}. As such, short pAgo systems mediate abortive infection.
Based on their phylogeny, short pAgos are subdivided in S1A, S1B, S2A, and S2B clades :ref{doi=10.1128/mBio.01935-18, 10.1016/j.tcb.2022.10.005}. In clade S1A and S1B (SPARSA) systems, APAZ is fused to an SIR2 domain. In clade S2A (SPARTA) systems, APAZ is fused to a TIR domain. Both SPARSA and SPARTA systems trigger cell death by depletion of NAD(P)+ :ref{doi=10.1016/j.cell.2022.03.012,10.1038/s41564-022-01239-0}. In S2B clade systems, APAZ is fused to one or more effector domains, including Mrr-like, DUF4365, RecG/DHS-like and other domains. In all clade S1A SPARSA systems, but also for certain other systems within other clades, the effector-APAZ is fused to the short pAgo. Based on their phylogeny, short pAgos are subdivided in S1A, S1B, S2A, and S2B clades :ref{doi=10.1128/mBio.01935-18,10.1016/j.tcb.2022.10.005}. In clade S1A and S1B (SPARSA) systems, APAZ is fused to an SIR2 domain. In clade S2A (SPARTA) systems, APAZ is fused to a TIR domain. Both SPARSA and SPARTA systems trigger cell death by depletion of NAD(P)+ :ref{doi=10.1016/j.cell.2022.03.012,10.1038/s41564-022-01239-0}. In S2B clade systems, APAZ is fused to one or more effector domains, including Mrr-like, DUF4365, RecG/DHS-like and other domains. In all clade S1A SPARSA systems, but also for certain other systems within other clades, the effector-APAZ is fused to the short pAgo.
### Pseudo-short pAgos ### Pseudo-short pAgos
Akin to short pAgos, pseudo-short pAgos are comprised of the MID and PIWI domains only :ref{doi=10.1016/j.tcb.2022.10.005}. However, they do not phylogenetically cluster with canonical short pAgos and do not colocalize with effector-APAZ proteins. Instead, certain pseudo-short are found across the long-A and long-B pAgo clades (e.g. Archaeoglobus fulgidus pAgo, a truncated long-B pAgo :ref{doi=10.1038/s41598-023-32600-w,10.1038/s41598-021-83889-4}), while others form a distinct branch in the phylogenetic pAgo tree (see SiAgo-like pAgos below). Akin to short pAgos, pseudo-short pAgos are comprised of the MID and PIWI domains only :ref{doi=10.1016/j.tcb.2022.10.005}. However, they do not phylogenetically cluster with canonical short pAgos and do not colocalize with effector-APAZ proteins. Instead, certain pseudo-short are found across the long-A and long-B pAgo clades (e.g. Archaeoglobus fulgidus pAgo, a truncated long-B pAgo :ref{doi=10.1038/s41598-023-32600-w,10.1038/s41598-021-83889-4}), while others form a distinct branch in the phylogenetic pAgo tree (see SiAgo-like pAgos below).
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