TRIM5α Restricts Flavivirus Replication by Targeting the Viral Protease for Proteasomal Degradation

Cell Rep. 2019 Jun 11;27(11):3269-3283.e6. doi: 10.1016/j.celrep.2019.05.040.


Tripartite motif-containing protein 5α (TRIM5α) is a cellular antiviral restriction factor that prevents early events in retrovirus replication. The activity of TRIM5α is thought to be limited to retroviruses as a result of highly specific interactions with capsid lattices. In contrast to this current understanding, we show that both human and rhesus macaque TRIM5α suppress replication of specific flaviviruses. Multiple viruses in the tick-borne encephalitis complex are sensitive to TRIM5α-dependent restriction, but mosquito-borne flaviviruses, including yellow fever, dengue, and Zika viruses, are resistant. TRIM5α suppresses replication by binding to the viral protease NS2B/3 to promote its K48-linked ubiquitination and proteasomal degradation. Importantly, TRIM5α contributes to the antiviral function of IFN-I against sensitive flaviviruses in human cells. Thus, TRIM5α possesses remarkable plasticity in the recognition of diverse virus families, with the potential to influence human susceptibility to emerging flaviviruses of global concern.

Keywords: TRIM5α; flavivirus; interferon; interferon stimulated genes; restriction factor; retrovirus; tick-borne encephalitis virus.

Publication types

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

MeSH terms

  • Animals
  • Antiviral Restriction Factors
  • Cats
  • Chlorocebus aethiops
  • Dendritic Cells / metabolism
  • Dendritic Cells / virology
  • Flavivirus / pathogenicity
  • Flavivirus / physiology
  • Flavivirus Infections / metabolism*
  • Flavivirus Infections / virology
  • HEK293 Cells
  • Humans
  • Peptide Hydrolases / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Proteolysis
  • Substrate Specificity
  • Tripartite Motif Proteins / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Vero Cells
  • Viral Proteins / metabolism*
  • Virus Replication*


  • Antiviral Restriction Factors
  • Tripartite Motif Proteins
  • Viral Proteins
  • TRIM5 protein, human
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex