TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity

Abstract

Antibodies are key molecules in the fight against infections. Although previously thought to mediate protection solely in the extracellular environment, recent research has revealed that antibody-mediated protection extends to the cytosolic compartment of cells. This postentry viral defense mechanism requires binding of the antibody to a cytosolic Fc receptor named tripartite motif containing 21 (TRIM21). In contrast to other Fc receptors, TRIM21 shows remarkably broad isotype specificity as it does not only bind IgG but also IgM and IgA. When viral pathogens coated with these antibody isotypes enter the cytosol, TRIM21 is rapidly recruited and efficient neutralization occurs before the virus has had the time to replicate. In addition, inflammatory signaling is induced. As such, TRIM21 acts as a cytosolic sensor that engages antibodies that have failed to protect against infection in the extracellular environment. Here, we summarize our current understanding of how TRIM21 orchestrates humoral immunity in the cytosolic environment.

A comprehensive review of the neonatal Fc receptor and its application in drug delivery

“…Other molecules that bind to the C H 2-C H 3 hinge region of Fc have also been recognized as potential blockers of the IgG-FcRn interaction, including the endogenous Fc receptor TRIM21 (Foss et al, 2015), the 13-amino acid cyclic peptide FcIII (Sockolosky et al, 2014), and the…”

“…TRIM21 shows remarkably broad isotype specificity as it does not only bind IgG, but also IgM and IgA, and acts as a cytosolic sensor that engages antibodies that have failed to protect against infection in the extracellular environment (Foss et al, 2015). FcIII, selected by a bacteriophage display screen, mimics the high affinity binding of Protein A or Protein G to the hinge region of Fc fragment of IgG molecules (DeLano et al, 2000;Feng et al, 2013).…”

“…(DeLano et al, 2000;Feng et al, 2013;Foss et al, 2015;Jaggi et al, 2007;Li et al, 2005;Linker, 1983;Liu et al, 2007;Ober et al, 2004a;Raghavan et al, 1994;Roopenian and Akilesh, 2007;Sockolosky et al, 2014;Sockolosky and Szoka, 2015;Strauch et al, 2014;Swiercz et al, 2014;Vaccaro et al, 2005;Zülfikar and Koç, 2014) Fc-fusion for vaccination and pathogen neutralization (a) Use of Fc-fused to model antigens.…”

Fcγ Receptor Function and the Design of Vaccination Strategies

“…While the Fab domains mediate highly specific interactions with the antigen through their CDR regions, the Fc domain has the capacity to interact with a wide range of receptors and molecules, each with distinct functional properties. In addition to the type I and type II FcγRs discussed in the previous section, Fc domain-interacting proteins also include FcRn, which modulates IgG half-life and recycling (Ghetie and Ward, 2000), TRIM21, a cytosolic receptor with antiviral activity (Foss et al, 2015), as well as the complement component C1q (Lund et al, 1996). Previous mutational analyses and crystallographic studies have precisely mapped the interaction sites of these proteins with the Fc domain and determined which regions of the Fc domain structure confer recognition by FcγRs (Shields et al, 2001; Sondermann et al, 2000; Sondermann et al, 2001).…”

Fc Receptors: Introduction

“…Foss et al . describe the roles and characteristics of the cytoplasmic FcR, TRIM21. This unique receptor has broad specificity for Ig isotypes and provides an intracellular‐based resistance, perhaps a ‘last line of defense’, which also has broad implications in vaccine design.…”