Abstract
Tripartite motif containing-21 (TRIM21) is a cytosolic ubiquitin ligase and antibody receptor that provides a last line of defense against invading viruses. It does so by acting as a sensor that intercepts antibody-coated viruses that have evaded extracellular neutralization and breached the cell membrane. Upon engagement of the Fc of antibodies bound to viruses, TRIM21 triggers a coordinated effector and signaling response that prevents viral replication while at the same time inducing an anti-viral cellular state. This dual effector function is tightly regulated by auto-ubiquitination and phosphorylation. Therapeutically, TRIM21 has been shown to be detrimental in adenovirus based gene therapy, while it may be favorably utilized to prevent tau aggregation in neurodegenerative disorders. In addition, TRIM21 may synergize with the complement system to block viral replication as well as transgene expression. TRIM21 can also be utilized as a research tool to deplete specific proteins in cells and zebrafish embryos. Here, we review our current biological understanding of TRIM21 in light of its versatile functions.
Highlights
Antibodies are a crucial part of the immune response to invading viruses, and induction of neutralizing antibodies is a primary goal of vaccination [1]
The analysis revealed that immune signaling is strictly dependent on Tripartite motif containing-21 (TRIM21) and its binding to antibody
The role of TRIM21 as a high affinity cytosolic Fc receptor has grown in significance in both disease and therapy
Summary
Antibodies are a crucial part of the immune response to invading viruses, and induction of neutralizing antibodies is a primary goal of vaccination [1]. Ad5 in complex with an Fc-engineered IgG1 rh9C12 variant with 100-fold improved binding to the TRIM21 PRYSPRY domain was reported to up-regulate the co-stimulatory molecules CD80, CD83, CD86, and HLA-DR as well as increase the production of pro-inflammatory cytokines by monocyte derived dendritic cells [62]. This translated into enhanced crosspriming and activation of CD8+ T cells at high multiplicity of infection. Non-pathogenic complexes such as host-derived proteins bound by antibody or antibody-coated beads are targeted by TRIM21 and activate its dual effector functions [20, 47]
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