Protein-primed initiation of RNA replication (=VPG capping)

Initiation of transcription/replication occurs via a protein primer-dependent mechanism. The protein linked in 5'-genomic RNA is called VPg (viral protein genome-linked) and replaces normal capping. In this way, recognition of viral 5' RNA by host antiviral receptors can be bypassed, and in some cases it replaces the cap function initiation of translation.

Enzymatic reaction:
Protein-primed terminal nucleotidyl transferase: RNA-dependent RNA polymerase (RdRp) attaches one or more nucleotides to a Tyrosine or asparagine in the target protein through a nucleotidyl-transferase reaction (Nucleotidylylation).

Picornavirus VPG can be removed by cellular TDP2/VPG unlinkase. This would favor viral replication: Either negative-strand or positive-strand RNA synthesis (or both) likely requires the removal of VPG from RNA for enterovirus infection to proceed efficiently . Furthermore, it would not trigger an antiviral response against uncapped mRNA (RIG -like receptors (RLR)), as this would occur in replication vesicles.