Gao_Her
Description
HerA and its associated effector (either Sir2 or DUF4297) represent a widespread defense system that responds to phage infection with rapid depletion of cellular NAD+ levels resulting in cell death and abortive infection.
The Gao Her anti-phage defense system, also known as Nezha, is composed of two genes, SirA, an NAD+ hydrolase and HerA, an helicase. These two proteins are associated in a stable octadecamer complex and are implicated in multiple enzymatic activities such as ATPase, NADase, helicase and nuclease.
The defense mechanism of the Gao Her system is debated between a bacterial cell death induction (Shen et al. 2023), and a temporary bacterial growth arrest followed by phage inactivation and population regrowth (Tang et al. 2023)
Molecular mechanisms
Although distinctions exist between characterized HerA-regulated systems from different bacteria, they appear to share both a common triggering mechanism and a common strategy resulting in abortive infection. Effector proteins (Sir2 or DUF4297) are catalytically inactive in isolation and require binding to HerA proteins for activation of their NADase and, potentially, nuclease activities. However, the NADase activity of effector proteins is antagonized by binding of ATP to HerA resulting in complete NADase inhibition at physiological levels of ATP. Depletion of ATP during phage infection alters the confirmation of HerA resulting in effector protein activation and rapid depletion of cellular NAD+ levels resulting in bacterial cell death (N/A) .
During phage infection, SIR2-HerA complex is activated and reduces intracellular ATP concentration. That leads to the activation of the NADase activity of the complex and causes bacterial death. Another article (Tang et al,. 2023) has demonstrated that this mechanism causes bacterial growth arrest. During phage infection, phage replication enhances the ATPase activity of Nezha and leads to the decrease of intracellular ATP concentration. Then, the low ATP intracellular concentration enables the activation of the multiple enzymatic activities as the NADase activity. It leads to the cell growth arrest, then the phage DNA is recognized by the system activating the nuclease activity of the complex. The phage DNA degradation enables the restoration of cellular ATP level, turning off the defense system and allowing the regrowth of the cells.
Example of genomic structure
A total of 3 subsystems have been described for the Gao_Her system.
Here are some examples found in the RefSeq database:
The Gao_Her_DUF system in Escherichia coli (GCF_023657935.1, NZ_CP098183) is composed of 2 proteins: DUF4297 (WP_064484828.1) and HerA_DUF (WP_064484829.1)
The Gao_Her_SIR system in Xanthomonas citri (GCF_018831325.1, NZ_CP029270) is composed of 2 proteins: SIR2 (WP_046831681.1) and HerA_SIR2 (WP_046831680.1)
The Gao_Her_SIR system in Staphylococcus aureus (GCF_008693765.1, NZ_CP044106) is composed of 2 proteins: SIR2 (WP_000513494.1) and HerA (WP_000555614.1)
Distribution of the system among prokaryotes
Structure
Experimentally determined structure
From (N/A) in Escherichia coli:
From (N/A) in Escherichia coli:
From (N/A) in Staphylococcus aureus (PDB 8YHO):