RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions

Nat Immunol. 2019 Dec;20(12):1610-1620. doi: 10.1038/s41590-019-0527-6. Epub 2019 Nov 18.


The initial response to viral infection is anticipatory, with host antiviral restriction factors and pathogen sensors constantly surveying the cell to rapidly mount an antiviral response through the synthesis and downstream activity of interferons. After pathogen clearance, the host's ability to resolve this antiviral response and return to homeostasis is critical. Here, we found that isoforms of the RNA-binding protein ZAP functioned as both a direct antiviral restriction factor and an interferon-resolution factor. The short isoform of ZAP bound to and mediated the degradation of several host interferon messenger RNAs, and thus acted as a negative feedback regulator of the interferon response. In contrast, the long isoform of ZAP had antiviral functions and did not regulate interferon. The two isoforms contained identical RNA-targeting domains, but differences in their intracellular localization modulated specificity for host versus viral RNA, which resulted in disparate effects on viral replication during the innate immune response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alphavirus Infections / genetics
  • Alphavirus Infections / immunology*
  • Feedback, Physiological
  • HEK293 Cells
  • Hep G2 Cells
  • Homeostasis
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferons / genetics*
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • RNA / genetics
  • RNA / metabolism*
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Sindbis Virus / physiology*
  • Virus Replication


  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Protein Isoforms
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Repressor Proteins
  • YLPM1 protein, human
  • RNA
  • Interferons