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 bacterial cell death induction (Shen et al. 2023), and temporary bacterial growth arrest followed by phage inactivation and population regrowth (Tang et al. 2023)
Molecular mechanisms
Although distinctions exist between Gao_Her systems from different bacteria, they share a common strategy for phage defense. Effector proteins (Sir2 or DUF4297) are catalytically inactive in isolation and require binding to HerA to activate their NADase and, potentially, nuclease activities. However, the NADase activity is antagonized by binding of ATP to HerA resulting in complete NADase inhibition at physiological ATP levels. During phage replication, ATP levels drop either directly due to phage utilization (S. aureus) or indirectly by activation of HerA's intrinsic ATPase activity (E. coli). Loss of ATP binding alters the confirmation of HerA resulting in effector protein activation and rapid depletion of cellular NAD+ levels causing bacterial growth arrest and viral replication arrest (Zhen et al. 2024)
The consequences of NAD+ depletion can vary. At high multiplicities of infection, (Shen et al,. 2023) observed E. coli death due to profound NAD+ depletion. In contrast, (Tang et al,. 2023) observed bacterial growth arrest and outgrowth. This is consistent with a model where recognition of additional phage components by some Gao_Her systems can activate additional effector protein activities. In E. coli, recognition of phage DNA stimulates nuclease activity in its effector protein resulting in phage DNA degradation, normalization of ATP levels, and regrowth of the bacterial population.
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):