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.

Keywords: Fc-receptor; TRIM21; antibodies; intracellular immunity; isotype; virus.

Fig. 1

Molecular basis for the TRIM 21–IgG interaction. Structural illustrations of the interaction between the human TRIM21 PRYSPRY (yellow) domain and the Fc part (blue) derived from human IgG1. The conserved C_H2-loop (252–256) and the C_H3-loop (429–436) of the Fc part are indicated while N297-linked glycans are shown in red. (A) Close-up view of the interactions formed between the C_H2 domain of IgG1 and the PRY element (upper panel) and the C_H3 domain and the SPRY element (lower panel). (B) The symmetric 2:1 complex in which two PRYSPRY domains bind one homodimeric Fc fragment at the C_H2–C_H3 interface. (C) An illustration showing insertion of conserved and protruding Fc-loop 429–436 into the hydrophobic binding pocket on the surface of TRIM21 PRYSPRY. The figure was prepared using PyMOL and based on the Protein Data Bank structure 2IWG (43).

Fig. 2

TRIM21 interacts with the Fc part of IgG, IgM, and IgA. (A) Close-up of the interaction network between the HNH motif of the IgG1 C_H3 loop (429–436) and TRIM21 PRYSPRY. (B, C) Structural models predicting the interactions of TRIM21 with IgM and IgA. Amino acid residues found in IgM and IgA (PNR and PLA, respectively), were modeled into the IgG1–PRYSPRY structure. The figure was prepared using PyMOL and based on the Protein Data Bank structure 2IWG (35,43).

Fig. 3

Cytosolic antiviral functions mediated by TRIM 21. (1) AdV5 in complex with antibodies interacts with CAR expressed on the surface of the target cell, which triggers endocytosis. (2) Exposure to acidic pH in the endosome induces a conformational change in the viral particle which results in membrane lysis and the AdV5 escapes into the cytosol bound to antibodies. Here, TRIM21 is rapidly recruited and binds to the Fc part of the antibodies leading to (3) sequential formation of K63 and K48-linked ubiquitin chains that result in targeting to VCP and the proteasomal machinery where Poh1 of the 19S regulatory subunit liberate (4) K63-linked ubiquitin chains and in turn is thought to activate the TAK1–TAB1–TAB2 and IKKα–IKKβ–NEMO enzyme complexes. (5) This results in degradation of the virus before it has time to replicate, and (6) activation of the transcription factor pathways NF-κB, AP-1, and IRF3/5/7 (7) accompanied by synthesis and secretion of pro-inflammatory cytokines and chemokines.