TRIM5α Restricts Flavivirus Replication by Targeting the Viral Protease for Proteasomal Degradation
Abhilash I. Chiramel,
Nicholas R. Meyerson,
Kristin L. McNally,
Rebecca M. Broeckel,
Vanessa R. Montoya,
Omayra Méndez-Solís,
Shelly J. Robertson,
Gail L. Sturdevant,
Kirk J. Lubick,
Vinod Nair,
Brian H. Youseff,
Robin M. Ireland,
Catharine M. Bosio,
Kyusik Kim,
Jeremy Luban,
Vanessa M. Hirsch,
R. Travis Taylor,
Fadila Bouamr,
Sara L. Sawyer,
Sonja M. Best
Affiliations
Abhilash I. Chiramel
Innate 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
Nicholas R. Meyerson
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA
Kristin L. McNally
Innate 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
Rebecca M. Broeckel
Innate 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
Vanessa R. Montoya
Innate 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
Omayra Méndez-Solís
Innate 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
Shelly J. Robertson
Innate 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
Gail L. Sturdevant
Innate 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
Kirk J. Lubick
Innate 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
Vinod Nair
Research Technology Branch, RML, NIAID, NIH, Hamilton, MT 59840, USA
Brian H. Youseff
Department of Medical Microbiology and Immunology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, Toledo, OH 43606, USA
Robin M. Ireland
Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, RML, NIAID, NIH, Hamilton, MT 59840, USA
Catharine M. Bosio
Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, RML, NIAID, NIH, Hamilton, MT 59840, USA
Kyusik Kim
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
Jeremy Luban
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
Vanessa M. Hirsch
Laboratory of Molecular Microbiology, NIAID, Bethesda, MD 20892, USA
R. Travis Taylor
Department of Medical Microbiology and Immunology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, Toledo, OH 43606, USA
Fadila Bouamr
Laboratory of Molecular Microbiology, NIAID, Bethesda, MD 20892, USA
Sara L. Sawyer
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA
Sonja M. Best
Innate 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; Corresponding author
Summary: 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. : The antiviral activity of TRIM5α is thought to be limited to retroviruses as a result of highly specific interactions with capsid lattices. Here, Chiramel et al. demonstrate that TRIM5α restricts replication of specific flaviviruses by binding and degrading the viral protease. Keywords: TRIM5α, flavivirus, retrovirus, interferon, restriction factor, retrovirus, interferon stimulated genes, tick-borne encephalitis virus
