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

Abhilash I Chiramel1, Nicholas R Meyerson2, Kristin L McNally1

  • 1Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories (RML), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, MT 59840, USA.

Cell Reports
|June 13, 2019
PubMed

Insights

Tripartite motif-containing protein 5α (TRIM5α) restricts flavivirus replication by targeting viral proteins for degradation. This finding reveals TRIM5α’s broader antiviral role beyond retroviruses, impacting flavivirus susceptibility.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Tripartite motif-containing protein 5α (TRIM5α) is a known cellular antiviral factor.
  • TRIM5α's known activity is primarily against retroviruses via capsid lattice interactions.
  • Its role in restricting non-retroviral viruses was previously unestablished.

Purpose of the Study:

  • To investigate the role of TRIM5α in the replication of flaviviruses.
  • To determine the mechanism by which TRIM5α restricts specific flaviviruses.
  • To assess the contribution of TRIM5α to innate immunity against flaviviruses.

Main Methods:

  • Utilized human and rhesus macaque TRIM5α.
  • Tested TRIM5α restriction against various flaviviruses (tick-borne encephalitis complex, yellow fever, dengue, Zika).
  • Investigated TRIM5α's mechanism involving viral protease NS2B/3, ubiquitination, and proteasomal degradation.
  • Assessed TRIM5α's role in Interferon-I (IFN-I) antiviral activity.

Main Results:

  • Human and rhesus macaque TRIM5α were found to suppress replication of specific flaviviruses.
  • Tick-borne encephalitis complex viruses were sensitive, while mosquito-borne flaviviruses (yellow fever, dengue, Zika) were resistant.
  • TRIM5α binds to the viral NS2B/3 protease, promoting its K48-linked ubiquitination and proteasomal degradation.
  • TRIM5α contributes to IFN-I antiviral activity against sensitive flaviviruses in human cells.

Conclusions:

  • TRIM5α exhibits plasticity in recognizing diverse virus families, extending beyond retroviruses.
  • TRIM5α restricts specific flaviviruses by degrading the NS2B/3 protease.
  • This antiviral activity has implications for understanding human susceptibility to emerging flaviviruses.
Keywords:
TRIM5αflavivirusinterferoninterferon stimulated genesrestriction factorretrovirustick-borne encephalitis virus

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