The perpetual arms race between bacteria and their viruses (phages) has given rise to diverse immune systems, including restriction-modification and CRISPR-Cas, which sense and degrade phage-derived nucleic acids. These complex systems rely upon production and maintenance of multiple components to achieve antiphage defense. However, the prevalence and effectiveness of minimal, single-component systems that cleave DNA remain unknown. Here, we describe a unique mode of nucleic acid immunity mediated by a single enzyme with nuclease and helicase activities, herein referred to as Nhi (nuclease-helicase immunity). This enzyme provides robust protection against diverse staphylococcal phages and prevents phage DNA accumulation in cells stripped of all other known defenses. Our observations support a model in which Nhi targets and degrades phage-specific replication intermediates. Importantly, Nhi homologs are distributed in diverse bacteria and exhibit functional conservation, highlighting the versatility of such compact weapons as major players in antiphage defense.
Sensor:Unknown
Activator:Unknown
Effector:Nucleic acid degrading (?)
Sensor:Phage protein sensing
Activator:Direct binding
Effector:Nucleic acid degrading
PFAM:PF01443, PF09848, PF13604
contributors:
-Alba Herrero del Valle
relevantAbstracts:
-doi:10.1016/j.chom.2022.03.001
-doi:10.1016/j.chom.2022.09.017
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# Nhi
## Description
The Nhi (nuclease-helicase immunity) system targets and degrades specific phage DNA replication intermediates :ref{doi=10.1016/j.chom.2022.03.001}. Nayeemul Bari et al. showed that Nhi from *Staphylococcus epidermidis* protects against a diverse panel of staphylococcal phages and Millman et al. showed that a protein Nhi-like (that shares the domain organization with Nhi but not the sequence) from *Bacillus cereus* protects against some Bacillus phages :ref{doi=10.1016/j.chom.2022.03.001,10.1016/j.chom.2022.09.017}.
## Molecular mechanisms
Nhi contains two domains, a nuclease and a helicase domain that are both needed for the anti-phage activity. The nuclease domain has 3′–5′ exonuclease and plasmid nicking activities while the helicase unwinds dsDNA biderctionally. Nhi specifically recognizes phage single-stranded DNA binding proteins (SSB) that cover the phage genome to target this DNA for degradation thanks to its helicase and nuclease domains :ref{doi=10.1016/j.chom.2022.03.001}.
