Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

Abstract

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...

Cryo-EM structures of tau filaments from Alzheimer’s disease

“…These characteristics are like those described previously for PHFs and SFs from AD brains 19 . Sarkosyl-insoluble material seeded aggregation of full-length human Tau in cultured cells 20 .…”

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…Such leakage may potentially interfere with normal functions of tau, although we have not detected any side effects of that antibody. It was also recently reported that an interaction of a tau antibody with cytosolic Fc receptor, TRIM21, inhibits seeded tau aggregation [65]. This finding suggests that tau antibodies may also have a cytosolic target to facilitate proteosomal clearance of misfolded tau.…”

“…Finally, the importance of antibody charge for intracellular access has been well studied for potential cancer antibody therapies but not for tau antibodies or similar approaches targeting other amyloids. We have recently shown that antibody charge can robustly affect antibody uptake into neurons [19,64], which may explain why some labs detect tau antibodies inside neurons [2,7–9,11,12,14,39,40,65], whereas others do not for different antibodies [34,41,43]. This issue has particular importance for clinical trials because the humanized antibodies are likely to have a different charge than the mouse antibodies that they are based on.…”

Intracellular Antiviral Immunity

“…Recently, it has been shown that TRIM21 can also inhibit tau seeds, which is the source of pathological tau that exhibits prion-like properties (Iqbal et al, 2015), in a manner similar to neutralizing antibody-bound viruses (McEwan et al, 2017). This suggests that the protection mediated by TRIM21 extends to nonclassical pathogens, such as proteopathic agents.…”