Ubiquitin-like modifier FAT10 attenuates RIG-I mediated antiviral signaling by segregating activated RIG-I from its signaling platform

Sci Rep. 2016 Mar 21:6:23377. doi: 10.1038/srep23377.


RIG-I is a key cytosolic RNA sensor that mediates innate immune defense against RNA virus. Aberrant RIG-I activity leads to severe pathological states such as autosomal dominant multi-system disorder, inflammatory myophathies and dermatomyositis. Therefore, identification of regulators that ensure efficient defense without harmful immune-pathology is particularly critical to deal with RIG-I-associated diseases. Here, we presented the inflammatory inducible FAT10 as a novel negative regulator of RIG-I-mediated inflammatory response. In various cell lines, FAT10 protein is undetectable unless it is induced by pro-inflammatory cytokines. FAT10 non-covalently associated with the 2CARD domain of RIG-I, and inhibited viral RNA-induced IRF3 and NF-kB activation through modulating the RIG-I protein solubility. We further demonstrated that FAT10 was recruited to RIG-I-TRIM25 to form an inhibitory complex where FAT10 was stabilized by E3 ligase TRIM25. As the result, FAT10 inhibited the antiviral stress granules formation contains RIG-I and sequestered the active RIG-I away from the mitochondria. Our study presented a novel mechanism to dampen RIG-I activity. Highly accumulated FAT10 is observed in various cancers with pro-inflammatory environment, therefore, our finding which uncovered the suppressive effect of the accumulated FAT10 during virus-mediated inflammatory response may also provide molecular clue to understand the carcinogenesis related with infection and inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DEAD Box Protein 58 / metabolism*
  • HEK293 Cells
  • Humans
  • Inflammation / metabolism*
  • Inflammation / virology*
  • Interferon Regulatory Factor-3 / metabolism
  • NF-kappa B / metabolism
  • Receptors, Immunologic
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitins / metabolism*


  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • NF-kappa B
  • Receptors, Immunologic
  • Transcription Factors
  • Tripartite Motif Proteins
  • UBD protein, human
  • Ubiquitins
  • TRIM25 protein, human
  • Ubiquitin-Protein Ligases
  • RIGI protein, human
  • DEAD Box Protein 58