Intracellular antibody signalling is regulated by phosphorylation of the Fc receptor TRIM21

• DOI: 10.7554/elife.32660
• Publication Date: 2018-04-18T05:00:11Z
• Authors: Claire Dickson; Adam J Fletcher; Marina Vaysburd; Ji-Chun Yang; Donna L Mallery; Jingwei Zeng; Christopher M Joh...; Stephen H McLaughlin; Mark Skehel; Sarah Maslen; James Cruickshank; Nicolas Huguenin-...; Jason W Chin; David Neuhaus; Leo C James
• Keywords: Structural Biology and Molecular Biophysics; 32 Biomedical and Clinical Sciences; Receptors, Fc; Mice; Receptors; structural biology; anzsrc-for: 31 Biological Sciences; Biology (General); Phosphorylation; anzsrc-for: 3204 Immunology; 0303 health sciences; Fc; anzsrc-for: 42 Health sciences; Fc receptors; anzsrc-for: 3101 Biochemistry and Cell Biology; Q; R; I-kappa B Kinase; 3. Good health; 3204 Immunology; Ribonucleoproteins; anzsrc-for: 0601 Biochemistry and Cell Biology; Medicine; Biotechnology; Signal Transduction; 570; QH301-705.5; 1.1 Normal biological development and functioning; Science; Protein Serine-Threonine Kinases; 3101 Biochemistry and Cell Biology; Antibodies; Cell Line; 03 medical and health sciences; anzsrc-for: 32 Biomedical and Clinical Sciences; Virology; molecular biophysics; Animals; Humans; human; Protein Processing; Prevention; Inflammatory and immune system; Post-Translational; E. coli; Gene Expression Regulation; Generic health relevance; Protein Processing, Post-Translational; 31 Biological Sciences

Cell surface Fc receptors activate inflammation and are tightly controlled to prevent autoimmunity. Antibodies also simulate potent immune signalling from inside the cell via the cytosolic antibody receptor TRIM21, but how this is regulated is unknown. Here we show that TRIM21 signalling is constitutively repressed by its B-Box domain and activated by phosphorylation. The B-Box occupies an E2 binding site on the catalytic RING domain by mimicking E2-E3 interactions, inhibiting TRIM21 ubiquitination and preventing immune activation. TRIM21 is derepressed by IKKβ and TBK1 phosphorylation of an LxxIS motif in the RING domain, at the interface with the B-Box. Incorporation of phosphoserine or a phosphomimetic within this motif relieves B-Box inhibition, promoting E2 binding, RING catalysis, NF-κB activation and cytokine transcription upon infection with DNA or RNA viruses. These data explain how intracellular antibody signalling is regulated and reveal that the B-Box is a critical regulator of RING E3 ligase activity.