Intracellular antibody-bound pathogens stimulate immune signaling via Fc-receptor TRIM21

Antibodies can be carried into the cell during pathogen infection where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we show that TRIM21 recognition of intracellular antibodies activates immune signaling. TRIM21 catalyses K63-ubiquitin chain formation, stimulating transcription factor pathways NF-κB, AP-1 and IRF3, IRF5, IRF7. Activation results in proinflammatory cytokine production, modulation of natural killer (NK) stress ligands and the induction of an antiviral state. Intracellular antibody signaling is abrogated by genetic deletion of TRIM21 and is recovered by ectopic TRIM21 expression. Antibody sensing by TRIM21 can be stimulated upon infection by DNA or RNA non-enveloped viruses or intracellular bacteria. The antibody-TRIM21 detection system provides potent, comprehensive innate immune activation, independent of known pattern recognition receptors.