TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity

Fan, Wenchun; Mar, Katrina B.; Sari, Levent; Gaszek, Ilona K.; Cheng, Qiang; Evers, B. Mark; Shelton, John M.; Wight-Carter, Mary; Siegwart, Daniel J.; Lin, Milo M.; Schoggins, John W.

doi:10.1016/j.cell.2021.04.047

Cited by 55 publications

(67 citation statements)

References 82 publications

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“…For PRRSV attachment assay, the siRNA-transfected cells were infected with PRRSV at an MOI of 10 and incubated at 4°C for 1 h. After adsorption, the unbound viruses were washed away with ice-cold PBS, and the relative level of cell-bound viral RNA was quantified by RT-qPCR ( 80 ). In parallel, PRRSV-bound cells were lysed for three freeze-thaw cycles and then subjected to a viral titration assay ( 81 ), or the cells seeded in glass dishes were infected with PRRSV (MOI = 10) and cultured at 4°C for 1 h. Then, the cell-bound virus was visualized using a mouse anti-GP5 antibody by confocal microscopy ( 82 ).…”

Section: Methodsmentioning

confidence: 99%

Tumor Susceptibility Gene 101 (TSG101) Contributes to Virion Formation of Porcine Reproductive and Respiratory Syndrome Virus via Interaction with the Nucleocapsid (N) Protein along with the Early Secretory Pathway

Zhang

Geng

et al. 2022

J Virol

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Porcine reproductive and respiratory syndrome virus (PRRSV) has caused huge economic losses to global swine industry. As an intracellular obligate pathogen, PRRSV exploits host cellular machinery to establish infection. The endocytic sorting complex required for transport (ESCRT) system has been shown to participate in different life cycle stages of multiple viruses. In the current study, a systematic small interference RNA (siRNA) screening assay identified that certain ESCRT components contributed to PRRSV infection. Among them, tumor susceptibility gene 101 (TSG101) was demonstrated to be important for PRRSV infection by knockdown and overexpression assays. TSG101 was further revealed to be involved in virion formation rather than viral attachment, internalization, RNA replication and nucleocapsid (N) protein translation within the first round of PRRSV life cycle. In detail, TSG101 was determined to specially interact with PRRSV N protein and take effect on its subcellular localization along with the early secretory pathway. Taken together, these results provide evidence that TSG101 is a pro-viral cellular factor for PRRSV assembly, which will be a promising target to interfere with the viral infection. IMPORTANCE PRRSV infection results in a serious swine disease affecting pig farming in the world. However, efficient prevention and control of PRRSV is hindered by its complicated infection process. Up to now, our understanding of PRRSV assembly during infection is especially limited. Here, we identified that TSG101, an ESCRT-I subunit, facilitated virion formation of PRRSV via interaction with the viral N protein along with the early secretory pathway. Our work actually expands the knowledge of PRRSV infection and provides a novel therapeutic target for prevention and control of the virus.

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Section: Methodsmentioning

confidence: 99%

Tumor Susceptibility Gene 101 (TSG101) Contributes to Virion Formation of Porcine Reproductive and Respiratory Syndrome Virus via Interaction with the Nucleocapsid (N) Protein along with the Early Secretory Pathway

Zhang

Geng

et al. 2022

J Virol

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“…S6 ). One proposed possibility is that these variants would alter the plasticity and enzymatic activity of 2C to gain a fitness advantage in vivo 9 . The N-terminal domain induces the hexamerization of 2C.…”

Section: Discussionmentioning

confidence: 99%

Structural insights into the viral proteins binding by TRIM7 reveal a general C-terminal glutamine recognition mechanism

Liang

Xiao

et al. 2022

Preprint

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The E3 ligase TRIM7 has emerged as a critical player in viral infection and pathogenesis. A recent study found that TRIM7 inhibits human enteroviruses through ubiquitination and proteasomal degradation of viral 2BC protein by targeting the 2C moiety of 2BC protein. Here, we report the crystal structures of TRIM7 in complex with 2C, where the C-terminal region of 2C is inserted into a positively charged groove of the TRIM7 PRY-SPRY domain. Structure-guided biochemical studies revealed the C-terminus glutamine residue of 2C as the primary determinant for TRIM7 binding. Such a glutamine-end motif binding mechanism can be successfully extended to other substrates of TRIM7. More importantly, leveraged by this finding, we were able to identify norovirus and SARS-CoV-2 proteins, and physiological proteins, as new TRIM7 substrates. We further show that TRIM7 may function as a restriction factor to promote the degradation of the viral proteins of norovirus and SARS-CoV-2, thereby restoring the Type I interferon immune response and inhibiting viral infection. Several crystal structures of TRIM7 in complex with SARS-CoV-2 proteins are also determined, and a conserved C-terminus glutamine-specific interaction is observed. These findings unveil a common recognition mode by TRIM7, providing the foundation for further mechanistic characterization of antiviral and cellular functions of TRIM7.

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“…A certain portion of these ubiquitin conjugates most likely constitutes viral proteins that could not achieve proper folding after synthesis and were, thus, co-translationally ubiquitinylated for proteasomal degradation [24]. Nevertheless, there are also reports showing that the UPS targets enteroviral proteins, including the RNA-dependent RNA polymerase of CVB3 and EV71, the protease 3C of EV71, and the membrane protein 2BC of CVB3, in order to hinder viral replication [8,[27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus B3 Exploits the Ubiquitin-Proteasome System to Facilitate Viral Replication

Voß

Braun

Bredow

et al. 2021

Viruses

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Infection by RNA viruses causes extensive cellular reorganization, including hijacking of membranes to create membranous structures termed replication organelles, which support viral RNA synthesis and virion assembly. In this study, we show that infection with coxsackievirus B3 entails a profound impairment of the protein homeostasis at virus-utilized membranes, reflected by an accumulation of ubiquitinylated proteins, including K48-linked polyubiquitin conjugates, known to direct proteins to proteasomal degradation. The enrichment of membrane-bound ubiquitin conjugates is attributed to the presence of the non-structural viral proteins 2B and 3A, which are known to perturb membrane integrity and can cause an extensive rearrangement of cellular membranes. The locally increased abundance of ubiquitinylated proteins occurs without an increase of oxidatively damaged proteins. During the exponential phase of replication, the oxidative damage of membrane proteins is even diminished, an effect we attribute to the recruitment of glutathione, which is known to be required for the formation of infectious virus particles. Furthermore, we show that the proteasome contributes to the processing of viral precursor proteins. Taken together, we demonstrate how an infection with coxsackievirus B3 affects the cellular protein and redox homeostasis locally at the site of viral replication and virus assembly.

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TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity

Cited by 55 publications

References 82 publications

Tumor Susceptibility Gene 101 (TSG101) Contributes to Virion Formation of Porcine Reproductive and Respiratory Syndrome Virus via Interaction with the Nucleocapsid (N) Protein along with the Early Secretory Pathway

Tumor Susceptibility Gene 101 (TSG101) Contributes to Virion Formation of Porcine Reproductive and Respiratory Syndrome Virus via Interaction with the Nucleocapsid (N) Protein along with the Early Secretory Pathway

Structural insights into the viral proteins binding by TRIM7 reveal a general C-terminal glutamine recognition mechanism

Coxsackievirus B3 Exploits the Ubiquitin-Proteasome System to Facilitate Viral Replication

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