AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization

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Host species have evolved mechanisms that can inhibit pathogen replication even after a cell has been successfully invaded. Here we show that tripartite-motif protein 21 (TRIM21), a ubiquitously expressed E3 ubiquitin ligase that targets viruses inside the cytosol, protects mice against fatal viral infection. Upon infection with mouse adenovirus-1, naive mice lacking TRIM21 succumb to encephalomyelitis within 7 d. In contrast, wild-type mice rapidly up-regulate TRIM21 and control viremia. Trim21 heterozygous mice have a haploinsufficiency phenotype in which reduced TRIM21 expression leads to a viral load that is higher than wild types but lower than knockouts. TRIM21 is a high-affinity antibody receptor that allows antibodies to operate inside an infected cell. In passive transfer experiments at high viral dose, antisera that fully protects wild-type mice fails to protect most Trim21 knockout animals. These results demonstrate that TRIM21 provides potent antiviral protection and forms an important part of the humoral immune response.

Section: Resultssupporting

confidence: 76%

Intracellular antibody receptor TRIM21 prevents fatal viral infection

Vaysburd

Watkinson

Cooper

et al. 2013

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“…Importantly, we observed that the inhibition of tau aggregation was more dependent on VCP than the proteasome. This is in contrast to adenovirus neutralization, in which proteasome and VCP activities are equally critical (1,5). VCP has been linked to both proteasomal degradation and autophagy; however, we did not observe any reduction in the neutralization of aggregation under conditions where autophagy was prevented.…”

Section: Discussioncontrasting

confidence: 53%

“…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).…”

mentioning

confidence: 99%

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

McEwan

Falcon

Vaysburd

et al. 2017

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153

163

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...

“…Many TRIM proteins (there are ∼100 members in humans) have reported roles in innate immunity (1). TRIM21 intercepts incoming, cytoplasmic antibody-coated pathogens and neutralizes them by mediating their VCP-and proteasome-dependent degradation (2,3). In addition, TRIM21 initiates a signaling cascade, resulting in the transcriptional up-regulation of inflammatory cytokines and a potent antiviral state in surrounding cells (4).…”

mentioning

confidence: 99%

Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21

Fletcher

Mallery

Watkinson

et al. 2015

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110

160

Tripartite motif (TRIM) 21 is a cytosolic antibody receptor that neutralizes antibody-coated viruses that penetrate the cell and simultaneously activates innate immunity. Here we show that the conjugation of TRIM21 with K63-linked ubiquitin (Ub-63 Ub) catalyzed by the sequential activity of nonredundant E2 Ub enzymes is required for its dual antiviral functions. TRIM21 is first labeled with monoubiquitin (monoUb) by the E2 Ube2W. The monoUb is a substrate for the heterodimeric E2 Ube2N/Ube2V2, resulting in TRIM21-anchored Ub-63 Ub. Depletion of either E2 abolishes Ub-63 Ub and Ub-48 Ub conjugation of TRIM21, NF-κB signaling, and virus neutralization. The formation of TRIM21-Ub-63 Ub precedes proteasome recruitment, and we identify an essential role for the 19S-resident and degradation-coupled deubiquitinase Poh1 in TRIM21 neutralization, signaling, and cytokine induction. This study elucidates a complex mechanism of step-wise ubiquitination and deubiquitination activities that allows contemporaneous innate immune signaling and neutralization by TRIM21.