Swine TRIM21 restricts FMDV infection via an intracellular neutralization mechanism

Fan, Wenchun; Zhang, Dong; Qian, Ping; Qian, Suhong; Wu, Mengyao; Chen, Huanchun; Li, Xiangmin

doi:10.1016/j.antiviral.2016.01.004

Cited by 40 publications

(40 citation statements)

References 51 publications

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“…Type I IFNs and many ISGs have been demonstrated to perform important role in suppressing FMDV infection (Dias et al, 2011;Fan et al, 2016;Xu et al, 2014). Our results show that ESD promotes type I IFN signal transduction (Fig.…”

Section: Discussionsupporting

confidence: 57%

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Esterase D enhances type I interferon signal transduction to suppress foot-and-mouth disease virus replication

Zhu

Cao

et al. 2016

Molecular Immunology

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Section: Discussionsupporting

confidence: 57%

“…Type I IFNs and ISGs also significantly confer protection against FMDV infection in porcine cells (Dias et al, 2011;Fan et al, 2016;Xu et al, 2014). SeV is a model virus for activating type I IFN signaling (Megyeri et al, 1995).…”

Section: Esd Enhances Sev-induced Promoter Activation Of Ifn-ǐmentioning

confidence: 99%

Esterase D enhances type I interferon signal transduction to suppress foot-and-mouth disease virus replication

Zhu

Cao

et al. 2016

Molecular Immunology

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“…Simultaneous with this degradation process, K63 ubiquitin chains released from TRIM21 by the 19S-associated deubiquitinase Poh1 stimulate NFκB, AP-1 and IRF3 immune transcription pathways, leading to potent activation of pro-inflammatory immunity56. TRIM21 antiviral activities have been demonstrated during infection by non-enveloped viruses from diverse families including adenoviridae, caliciviridae and picornaviridae and the intracellular bacteria Salmonella678. TRIM21 function provides an important component of protective antibody immunity in vivo .…”

mentioning

confidence: 99%

Antibody-antigen kinetics constrain intracellular humoral immunity

Bottermann

Lode

Watkinson

et al. 2016

Sci Rep

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During infection with non-enveloped viruses, antibodies stimulate immunity from inside cells by activating the cytosolic Fc receptor TRIM21. This intracellular humoral response relies on opsonized viral particles reaching the cytosol intact but the antigenic and kinetic constraints involved are unknown. We have solved the structure of a potent TRIM21-dependent neutralizing antibody in complex with human adenovirus 5 hexon and show how these properties influence immune activity. Structure-guided mutagenesis was used to generate antibodies with 20,000-fold variation in affinity, on-rates that differ by ~50-fold and off-rates by >175-fold. Characterization of these variants during infection revealed that TRIM21-dependent neutralization and NFκB activation was largely unaffected by on-rate kinetics. In contrast, TRIM21 antiviral activity was exquisitely dependent upon off-rate, with sub-μM affinity antibodies nevertheless unable to stimulate signaling because of fast dissociation kinetics. These results define the antibody properties required to elicit an efficient intracellular immune response during viral infection.

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“…The broad tissue expression of TRIM21 and its ultrahigh affinity for Fc imply that intracellular antibodies will be bound by TRIM21 whenever they occur. Numerous intracellular entities may therefore be targeted by TRIM21, including DNA and RNA viruses (1,11,12), cytosolic bacteria (3), and soluble host proteins, including an Fc fragment (5) and a cis-tau conformer (13). However, it is not known whether self-propagating protein assemblies are susceptible to neutralization by TRIM21.…”

mentioning

confidence: 99%

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

McEwan

Falcon

Vaysburd

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

141

145

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Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubuleassociated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.T he cell's ability to identify intracellular viruses and bacteria relies on the detection of pathogen-associated molecular patterns (PAMPs) by specialized host receptors. Although highly effective at detecting microbial pathogens, this strategy is poorly equipped to identify host-derived pathogenic species such as aggregated proteins. As an alternative to PAMP detection, recent work has demonstrated that mammalian cells can use hostderived serum proteins, which are normally excluded from the cell interior, to target invading viruses and bacteria in the cytosol. For instance, nonenveloped viruses and bacteria carry antibodies with them into the cytoplasm during infection. These translocated antibodies are then sensed by the cytoplasmically expressed antibody receptor TRIM21 (tripartite motif protein 21), which binds with subnanomolar affinity to the antibody Fc domain (1-4). After binding to antibody, TRIM21 triggers a potent neutralization response that inhibits viral infection. Neutralization of infection is accompanied by degradation of viral components, which requires the activity of the proteasome and the molecular unfoldase, valosincontaining protein (VCP) or p97 (1, 5). Detection of viruses and bacteria by TRIM21 does not rely on microbial PAMPs, as model substrates such as antibody-coated latex beads can be bound and detected by TRIM21 (1, 3). We therefore hypothesized that the intracellular innate immune system could be repurposed to recognize and degrade host-derived pathogenic proteins.Microtubule-associated protein tau occurs in an assembled and hyperphosphorylated state in the cytoplasm of neurons and glial cells in Alzheimer's disease (AD), progressive supranuclear palsy, chronic traumatic encep...

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Swine TRIM21 restricts FMDV infection via an intracellular neutralization mechanism

Cited by 40 publications

References 51 publications

Esterase D enhances type I interferon signal transduction to suppress foot-and-mouth disease virus replication

Esterase D enhances type I interferon signal transduction to suppress foot-and-mouth disease virus replication

Antibody-antigen kinetics constrain intracellular humoral immunity

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

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