title: Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation.
abstract: Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated 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.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; wmcewan@mrc-lmb.cam.ac.uk mg@mrc-lmb.cam.ac.uk lcj@mrc-lmb.cam.ac.uk.
authors.forename: William A
authors.identifier: 0000-0002-4408-0407
authors.initials: WA
authors.lastname: McEwan
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Falcon
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
authors.forename: Marina
authors.initials: M
authors.lastname: Vaysburd
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
authors.forename: Dean
authors.initials: D
authors.lastname: Clift
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Oblak
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; wmcewan@mrc-lmb.cam.ac.uk mg@mrc-lmb.cam.ac.uk lcj@mrc-lmb.cam.ac.uk.
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; wmcewan@mrc-lmb.cam.ac.uk mg@mrc-lmb.cam.ac.uk lcj@mrc-lmb.cam.ac.uk.
authors.forename: Leo C
authors.initials: LC
authors.lastname: James
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D057165:Proteostasis Deficiencies / Q000378:metabolism / Q000517:prevention & control; D011961:Receptors, Fc / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D000099207:SS-A Antigen
chemical_list: D057134:Antibodies, Neutralizing; D046988:Proteasome Endopeptidase Complex; D066329:Protein Aggregates; D011961:Receptors, Fc; D012261:Ribonucleoproteins; D016875:tau Proteins; D000099207:SS-A Antigen; C054369:MAPT protein, human; C558298:Mapt protein, mouse
keywords: antibodies; immunoreceptors; intracellular immunity; neurodegeneration; tau