TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation

Chiramel, Abhilash I.; Meyerson, Nicholas R.; McNally, Kristin L.; Broeckel, Rebecca; Montoya, Vanessa R.; Méndez-Solís, Omayra; Robertson, Shelly J.; Sturdevant, Gail L.; Lubick, Kirk J.; Nair, Vinod; Youseff, Brian H.; Ireland, Robin; Bosio, Catharine M.; Kim, Kyusik; Luban, Jeremy; Hirsch, Vanessa M.; Taylor, R. Travis; Bouamr, Fadila; Sawyer, Sara L.; Best, Sonja M.

doi:10.1101/605345

Cited by 8 publications

(12 citation statements)

References 46 publications

(64 reference statements)

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“…ns, non-significant (p > 0.05); *p < 0.05, **p < 0.01, ***p < 0.001 longer duration in human astrocytes than in human neurons. The antiviral programs of the two cell types were also notably distinct, as exemplified by selective upregulation of the genes encoding viperin and TRIM5α, well-known for their anti-TBEV and anti-flavivirus activities [37][38][39], in human astrocytes. In sum, our results revealed a stronger and broader antiviral response in human astrocytes than in human neurons, in keeping with their differential susceptibility to TBEV infection, astrocytes being more resistant and neurons more susceptible.…”

Section: Differential Antiviral Response In Human Neurons and Human Amentioning

confidence: 99%

Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Fares

Cochet-Bernoin

Gonzalez

et al. 2020

J Neuroinflammation

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Background: Tick-borne encephalitis virus (TBEV) is a member of the Flaviviridae family, Flavivirus genus, which includes several important human pathogens. It is responsible for neurological symptoms that may cause permanent disability or death, and, from a medical point of view, is the major arbovirus in Central/Northern Europe and North-Eastern Asia. TBEV tropism is critical for neuropathogenesis, yet little is known about the molecular mechanisms that govern the susceptibility of human brain cells to the virus. In this study, we sought to establish and characterize a new in vitro model of TBEV infection in the human brain and to decipher cell type-specific innate immunity and its relation to TBEV tropism and neuropathogenesis.Method: Human neuronal/glial cells were differentiated from neural progenitor cells and infected with the TBEV-Hypr strain. Kinetics of infection, cellular tropism, and cellular responses, including innate immune responses, were characterized by measuring viral genome and viral titer, performing immunofluorescence, enumerating the different cellular types, and determining their rate of infection and by performing PCR array and qRT-PCR. The specific response of neurons and astrocytes was analyzed using the same approaches after enrichment of the neuronal/glial cultures for each cellular subtype. Results: We showed that infection of human neuronal/glial cells mimicked three major hallmarks of TBEV infection in the human brain, namely, preferential neuronal tropism, neuronal death, and astrogliosis. We further showed that these cells conserved their capacity to mount an antiviral response against TBEV. TBEV-infected neuronal/glial cells, therefore, represented a highly relevant pathological model. By enriching the cultures for either neurons or astrocytes, we further demonstrated qualitative and quantitative differential innate immune responses in the two cell types that correlated with their particular susceptibility to TBEV. Conclusion:Our results thus reveal that cell type-specific innate immunity is likely to contribute to shaping TBEV tropism for human brain cells. They describe a new in vitro model for in-depth study of TBEV-induced neuropathogenesis and improve our understanding of the mechanisms by which neurotropic viruses target and damage human brain cells.

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Section: Differential Antiviral Response In Human Neurons and Human Amentioning

confidence: 99%

Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Fares

Cochet-Bernoin

Gonzalez

et al. 2020

J Neuroinflammation

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“…Cooperation with deubiquitinases (DUBs) allows for the recycling of ubiquitin chains, making the ubiquitin-proteasome system (UPS) a powerful tool for both protein turnover as well as removal of unwanted cellular and viral components [72]. In addition to its known roles in retroviral restriction, TRIM5α has now been described suppressing flavivirus replication with the help of the proteasome [73]. In a recent screen against several members of both tick-and mosquito-borne viruses, TRIM5α showed restriction against specific members of the TBEV serogroup including TBEV (Sofjin strain), Kyasanur Forest disease virus (KFDV), and LGTV but not against WNV, dengue virus (DENV) or ZIKV [73].…”

Section: Proteasome-dependent Antiviral Mechanismsmentioning

confidence: 99%

“…In addition to its known roles in retroviral restriction, TRIM5α has now been described suppressing flavivirus replication with the help of the proteasome [73]. In a recent screen against several members of both tick-and mosquito-borne viruses, TRIM5α showed restriction against specific members of the TBEV serogroup including TBEV (Sofjin strain), Kyasanur Forest disease virus (KFDV), and LGTV but not against WNV, dengue virus (DENV) or ZIKV [73]. By targeting the viral NS2B/3 protease, TRIM5α is able to hamper viral replication through conjugation of K48-linked polyubiquitin that targets the viral protease for proteasomal degradation [73].…”

Section: Proteasome-dependent Antiviral Mechanismsmentioning

confidence: 99%

“…In a recent screen against several members of both tick-and mosquito-borne viruses, TRIM5α showed restriction against specific members of the TBEV serogroup including TBEV (Sofjin strain), Kyasanur Forest disease virus (KFDV), and LGTV but not against WNV, dengue virus (DENV) or ZIKV [73]. By targeting the viral NS2B/3 protease, TRIM5α is able to hamper viral replication through conjugation of K48-linked polyubiquitin that targets the viral protease for proteasomal degradation [73]. Herpesviruses are also susceptible to TRIM5α, with the replication and transcription activator (Rta) from Epstein-Barr virus (EBV) as an identified target [74].…”

Section: Proteasome-dependent Antiviral Mechanismsmentioning

confidence: 99%

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To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Hage

Rajsbaum

2019

Journal of General Virology

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The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target's function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host-virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.

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“…Finally, we would like to suggest that Fv1 is not alone in its evolutionary plasticity. Other antiviral factors, for example members of the Trim family (50,51), protecting against other types of virus (52), seem likely to exhibit significant sequence variation driven by circulating viruses.…”

Section: Discussionmentioning

confidence: 99%

Duplication and divergence of the retrovirus restriction geneFv1inMus carolimice allows protection from multiple retroviruses

Yap

Young

Varnaitė

et al. 2019

Preprint

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Viruses and their hosts are locked in an evolutionary race where resistance to infection is acquired by the hosts while viruses develop strategies to circumvent these host defenses. Forming one arm of the host defense armory are cell autonomous restriction factors like Fv1. Originally described as protecting laboratory mice from infection by murine leukemia virus (MLV), Fv1s from some wild mice have also been found to restrict non-MLV retroviruses, suggesting an important role in the protection against viruses in nature. To begin to understand how restriction factors evolve, we surveyed the Fv1 genes of wild mice trapped in Thailand and characterized their restriction activities against a panel of retroviruses. An extra copy of the Fv1 gene, named Fv7, was found on chromosome 6 of three closely related Asian species of mice (Mus caroli, M. cervicolor and M. cookii). The presence of flanking repeats suggested it arose by LINE-mediated retrotransposition.A high degree of natural variation was observed in both Fv1 and Fv7, including numerous single nucleotide polymorphisms resulting in altered amino acids, as well as insertions and deletions that changed the length of the reading frames. These genes exhibited a range of restriction phenotypes with activities directed against feline foamy virus (FFV), equine infectious anemia virus (EIAV) and MLV. It seems likely, at least in the case of M. caroli, that the observed gene duplication confers protection against multiple viruses not possible with a single restriction factor. We suggest that EIAV-, FFV-and MLV-like viruses are endemic within these populations, driving the evolution of the Fv1 and Fv7 genes. Author SummaryDuring the passage of time all vertebrates will be exposed to infection by a variety of different kinds of virus. To meet this threat, a variety of genes for natural resistance to viral infection have evolved. The prototype of such so-called restriction factors is encoded by the mouse Fv1 gene, which acts to block the life cycle of retroviruses at a stage between virus entry into the cell and integration of the viral genetic material into the nuclear DNA. We have studied the evolution of this gene in certain species of wild mice from South East Asia and describe an example where a duplication of the Fv1 gene has taken place. The two copies of the gene, initially identical, have evolved separately allowing the development of resistance to two rather different kinds of retroviruses, lentiviruses and spumaviruses. Independent selection for resistance to these two kinds of retrovirus suggests that such mice are repeatedly exposed to never-before-reported pathogenic retroviruses of these genera.

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TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation

Cited by 8 publications

References 46 publications

Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Duplication and divergence of the retrovirus restriction geneFv1inMus carolimice allows protection from multiple retroviruses

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