Cytosolic antibody receptor TRIM21 is required for effective tau immunotherapy in mouse models

Aggregates of the protein tau are proposed to drive pathogenesis in neurodegenerative diseases. Tau can be targeted by using passively transferred antibodies (Abs), but the mechanisms of Ab protection are incompletely understood. In this work, we used a variety of cell and animal model systems and showed that the cytosolic Ab receptor and E3 ligase TRIM21 (T21) could play a role in Ab protection against tau pathology. Tau-Ab complexes were internalized to the cytosol of neurons, which enabled T21 engagement and protection against seeded aggregation. Ab-mediated protection against tau pathology was lost in mice that lacked T21. Thus, the cytosolic compartment provides a site of immunotherapeutic protection, which may help in the design of Ab-based therapies in neurodegenerative disease. Description Tau and TRIM21 Aggregation of the protein tau inside neurons contributes to common neurodegenerative conditions, including Alzheimer’s disease. Mukadam et al. demonstrate that mouse models of tau pathology can be treated using anti-tau antibodies by engaging the cytosolic antibody receptor TRIM21 (see the Perspective by Nisbet). Tau assemblies can transit into cells with antibodies attached, thereby bringing TRIM21 and antibody into contact. As an atypical receptor, TRIM21 possesses E3 ubiquitin ligase activity and can mediate the inactivation of these tau assemblies that would otherwise act as seeds for further aggregation. The discovery of this pathway could enable optimization of future immunotherapies. —SMH Passive transfer of antibodies targeting tau reduce tau pathology through the cytosolic antibody receptor and E3 ligase TRIM21.