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

Abstract

Proteins containing a RNB domain, originally identified in E. coli RNase II, are widely present throughout the tree of life. Many RNB proteins are endowed with 3'-5' exoribonucleolytic activity but some have lost catalytic function during evolution. Database searches identified a new RNB domain containing protein in human: HELZ2. Analysis of genomic and expression data 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 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'-5' ribonucleolytic action. The expression characteristics and biochemical properties of HELZ2 support a role for this factor in response to viruses and/or mobile elements.

Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection

“…Another unexpected finding is the high enrichment of HELZ2 in both genome-wide and targeted screens. HELZ2 is an interferon-stimulated helicase and nuclear factor coactivator [ 55,56,94 ] with previously described antiviral activity in the context of direct DENV and to a lesser extent, Zika virus, infection [ 55,56 ]. Thus, HELZ2 may be among a growing set of interferonstimulated genes with both antiviral and proviral functions [ 55,95 ].…”

Unraveling biological processes and EGFR pathway regulation by the protein tyrosine phosphatase PTPRH in non-small cell lung cancer

“…Hence, PTPRH dimers may be present in our cell lines or PTPRH monomers are biotinylating themselves. Even though some of the interacting proteins herein reported are mostly found in the nucleus, there is also evidence of the location of these proteins in the cytosol or the mebrane [64][65][66] . Since we did not observe the presence of the phosphatase in the nucleus of our transduced cells but rather in the cytosol and plasma membrane, we anticipate that the interaction is mediated in these cellular compartments.…”