Attenuation of the Innate Immune Response against Viral Infection Due to ZNF598-Promoted Binding of FAT10 to RIG-I

Cell Rep. 2019 Aug 20;28(8):1961-1970.e4. doi: 10.1016/j.celrep.2019.07.081.


Excessive innate immune response is harmful to the host, and aberrant activation of the cytoplasmic viral RNA sensors RIG-I and MDA5 leads to autoimmune disorders. ZNF598 is an E3 ubiquitin ligase involved in the ribosome quality control pathway. It is also involved in the suppression of interferon (IFN)-stimulated gene (ISG) expression; however, its underlying mechanism is unclear. In this study, we show that ZNF598 is a negative regulator of the RIG-I-mediated signaling pathway, and endogenous ZNF598 protein binds to RIG-I. ZNF598 ubiquitin ligase activity is dispensable for the suppression of RIG-I signaling. Instead, ZNF598 delivers a ubiquitin-like protein FAT10 to the RIG-I protein, resulting in the inhibition of RIG-I polyubiquitination, which is required for triggering downstream signaling to produce type I IFN. Moreover, ZNF598-mediated suppression is abrogated by FAT10 knockout. Our data elucidate the mechanism by which ZNF598 inhibits RIG-I-mediated innate immune response.

Keywords: FAT10; RIG-I; ZNF598; innate immunity; interferon; ubiquitin; virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism*
  • Cell Line
  • Cytokines / metabolism
  • DEAD Box Protein 58 / metabolism*
  • Humans
  • Immunity, Innate*
  • Protein Binding
  • Receptors, Immunologic
  • Signal Transduction
  • Ubiquitin / metabolism
  • Ubiquitination
  • Ubiquitins / metabolism*
  • Virus Diseases / immunology*


  • Carrier Proteins
  • Cytokines
  • Receptors, Immunologic
  • UBD protein, human
  • Ubiquitin
  • Ubiquitins
  • ZNF598 protein, human
  • RIGI protein, human
  • DEAD Box Protein 58