The cyclic pyrimidines 3',5'-cyclic cytidine monophosphate (cCMP) and 3',5'-cyclic uridine monophosphate (cUMP) have been reported in multiple organisms and cell types. As opposed to the cyclic nucleotides 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP), which are second messenger molecules with well-established regulatory roles across all domains of life, the biological role of cyclic pyrimidines has remained unclear. Here we report that cCMP and cUMP are second messengers functioning in bacterial immunity against viruses. We discovered a family of bacterial pyrimidine cyclase enzymes that specifically synthesize cCMP and cUMP following phage infection and demonstrate that these molecules activate immune effectors that execute an antiviral response. A crystal structure of a uridylate cyclase enzyme from this family explains the molecular mechanism of selectivity for pyrimidines as cyclization substrates. Defense systems encoding pyrimidine cyclases, denoted here Pycsar (pyrimidine cyclase system for antiphage resistance), are widespread in prokaryotes. Our results assign clear biological function to cCMP and cUMP as immunity signaling molecules in bacteria.
Sensor:Monitoring of the host cell machinery integrity
Activator:Direct
DNA viruses and retroviruses consume large quantities of deoxynucleotides (dNTPs) when replicating. The human antiviral factor SAMHD1 takes advantage of this vulnerability in the viral lifecycle, and inhibits viral replication by degrading dNTPs into their constituent deoxynucleosides and inorganic phosphate. Here, we report that bacteria use a similar strategy to defend against bacteriophage infection. We identify a family of defensive bacterial deoxycytidine triphosphate (dCTP) deaminase proteins that convert dCTP into deoxyuracil nucleotides in response to phage infection. We also identify a family of phage resistance genes that encode deoxyguanosine triphosphatase (dGTPase) enzymes, which degrade dGTP into phosphate-free deoxyguanosine and are distant homologues of human SAMHD1. Our results suggest that bacterial defensive proteins deplete specific deoxynucleotides (either dCTP or dGTP) from the nucleotide pool during phage infection, thus starving the phage of an essential DNA building block and halting its replication. Our study shows that manipulation of the dNTP pool is a potent antiviral strategy shared by both prokaryotes and eukaryotes..
Sensor:Host integrity monitoring
Activator:Unknown
Effector:Nucleotide modifying
PFAM:PF00383, PF14437
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contributors:
-Nathalie Bechon
relevantAbstracts:
-doi:10.1038/s41564-022-01162-4
-doi:10.1038/s41564-022-01158-0
# dCTPdeaminase
## Description
dCTPdeaminase is a family of systems. dCTPdeaminase from Escherichia coli has been shown to provide resistance against various lytic phages when express heterologously in another Escherichia coli.
dCTPdeaminase is a family of systems. dCTPdeaminase from Escherichia coli has been shown to provide resistance against various lytic phages when expressed heterologously in another Escherichia coli by degrading the pool of dCTP available for phage DNA replication.
This system is mostly found in Proteobacteria but a few examples also exist in Acidobacteria, Actinobacteria, Bacteroidetes, Cyanobacteria, Firmicutes, Planctomyces, and Verrucomicrobia.
Those systems can be found in plasmids (around 8%).
## Mechanism
When activated by a phage infection, dCTPdeaminase, will convert deoxycytidine (dCTP/dCDP/dCMP) into deoxyuridine.
This action will deplete the pool of CTP nucleotide necessary for the phage replication and will stop the infection.
The trigger for dCTPdeaminase may be linked to the shutoff of RNAP (σS-dependent host RNA polymerase) that occur during phage infections.
The trigger for dCTPdeaminase may be linked to the shutoff of RNAP ($\sigma$ S-dependent host RNA polymerase) that occur during phage infections.
