Abstract
TRIM21 has emerged as an atypical Fc receptor that is broadly conserved and widely expressed in the cytoplasm of mammalian cells. Viruses that traffic surface-bound antibodies into the cell during infection recruit TRIM21 via a high affinity interaction between Fc and TRIM21 PRYSPRY domain. Following binding of intracellular antibody, TRIM21 acts as both antiviral effector and sensor for innate immune signalling. These activities serve to reduce viral replication by orders of magnitude in vitro and contribute to host survival during in vivo infection. Neutralization occurs rapidly after detection and requires the activity of the ubiquitin-proteasome system. The microbial targets of this arm of intracellular immunity are still being identified: TRIM21 activity has been reported following infection by several non-enveloped viruses and intracellular bacteria. These findings extend the sphere of influence of antibodies to the intracellular domain and have broad implications for immunity. TRIM21 has been implicated in the chronic auto-immune condition systemic lupus erythematosus and is itself an auto-antigen in Sjögren’s syndrome. This review summarises our current understanding of TRIM21’s role as a cytosolic Fc receptor and briefly discusses pathological circumstances where intracellular antibodies have been described, or are hypothesized to occur, and may benefit from further investigations of the role of TRIM21.
Highlights
Antibodies are secreted by plasma cells into the extracellular environment whereupon they are excluded from the cytoplasmic environment by cell-limiting and endosomal membranes.IgG molecules that become internalized via endocytosis may be degraded in the endo-lysosomal pathway or returned to circulation by FcRn after entering the recycling endosome pathway [1].In this way, IgG molecules are maintained at high concentration in plasma with a half-life of around 3 weeks
tripartite motif 21 (TRIM21) was first demonstrated to interact with IgG1 Fc domain in a yeast two-hybrid screen [2] but the significance of this interaction remained cryptic until adenovirus particles were demonstrated to import antibodies during infection [3]
From analysis of these antibodies, it was concluded that the signaling response of TRIM21 requires a high affinity Fc:PRYSPRY interaction but that the neutralization response is less sensitive to reduced affinity
Summary
Antibodies are secreted by plasma cells into the extracellular environment whereupon they are excluded from the cytoplasmic environment by cell-limiting and endosomal membranes. IgG molecules that become internalized via endocytosis may be degraded in the endo-lysosomal pathway or returned to circulation by FcRn after entering the recycling endosome pathway [1]. In this way, IgG molecules are maintained at high concentration in plasma with a half-life of around 3 weeks. Upon entry to the cytoplasm, antibody-coated virus particles are rapidly detected owing to the ultra-high affinity interaction between TRIM21 and antibody Fc [4,5]. A role for TRIM21 is emerging in which it surveys the intracellular environment for antibody, which serves as a potent proxy signal for compromised cellular integrity when in the cytoplasm.
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