SARS-CoV-2 and many other viruses use a phenomenon called programmed ribosomal frameshifting. It allows the viruses to use their host cells for the production of multiple, unique proteins from a single mRNA fragment. This works by shifting the “reading frame” of the genetic code, i.e., starting at a different nucleotide, which then encodes for different amino acids and builds a different protein. This “trick” allows viruses to fit more information into a shorter amount of genetic material.

Neva Caliskan, Helmholtz Centre for Infection Research, Würzburg, and University of Würzburg, Germany, and colleagues have found that the host protein ZAP (zinc-finger antiviral protein) can act as an inhibitor of SARS-CoV-2 programmed ribosomal frameshifting. ZAP had already been known as an immunomodulatory and antiviral protein. It exists in a short (ZAP-S) and a long form (ZAP-L).

The team found that ZAP-S binds to the viral RNA that triggers the frameshift. This hinders the production of enzymes that are important for viral replication in host cells. The researchers demonstrated that host cells with elevated levels of ZAP-S strongly inhibit viral replication and show an approximately 20-fold reduction in the amount of virus they produce. The presence—or absence—of the protein could, thus, also be an indicator of whether an infection leads to mild or severe disease. Understanding how proteins such as ZAP interfere with the ribosomal frameshift of SARS-CoV-2 could be useful for the design of new antiviral medications.

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• The short isoform of the host antiviral protein ZAP acts as an inhibitor of SARS-CoV-2 programmed ribosomal frameshifting,
  Matthias M. Zimmer, Anuja Kibe, Ulfert Rand, Lukas Pekarek, Liqing Ye, Stefan Buck, Redmond P. Smyth, Luka Cicin-Sain, Neva Caliskan,
  Nat. Commun. 2021.
  https://doi.org/10.1038/s41467-021-27431-0

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