HELZ2: a new, interferon-regulated, human 3 & PRIME;-5 & PRIME; exoribonuclease of the RNB family is expressed from a non-canonical initiation codon

Proteins containing a RNB domain, originally identified in Escherichia coli RNase II, are widely present throughout the tree of life. Many RNB proteins have 3 & PRIME;-5 & PRIME; exoribonucleolytic activity but some have lost catalytic activity during evolution. Database searches identified a new RNB domain-containing protein in human: HELZ2. Analysis of genomic and expression data combined with evolutionary information suggested that the human HELZ2 protein is produced from an unforeseen non-canonical initiation codon in Hominidae. This unusual property was confirmed experimentally, extending the human protein by 247 residues. Human HELZ2 was further shown to be an active ribonuclease despite the substitution of a key residue in its catalytic center. HELZ2 RNase activity is lost in cells from some cancer patients as a result of somatic mutations. HELZ2 harbors also two RNA helicase domains and several zinc fingers and its expression is induced by interferon treatment. We demonstrate that HELZ2 is able to degrade structured RNAs through the coordinated ATP-dependent displacement of duplex RNA mediated by its RNA helicase domains and its 3 & PRIME;-5 & PRIME; ribonucleolytic action. The expression characteristics and biochemical properties of HELZ2 support a role for this factor in response to viruses and/or mobile elements.

Automated summary

Proteins with RNB domain are present across various species, and a new RNB protein, HELZ2, was identified in humans. HELZ2 protein in humans is produced from an unexpected non-canonical initiation codon and can function as an active ribonuclease despite a key residue substitution. The activity of HELZ2 as a ribonuclease is lost in cancer cells due to somatic mutations. HELZ2 also contains RNA helicase domains and zinc fingers, and its expression is induced by interferon treatment. It is involved in degrading structured RNAs through ATP-dependent displacement mediated by its RNA helicase domains and ribonucleolytic action.