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

Dickson, C. et al. (2018) Intracellular antibody signalling is regulated by phosphorylation of the Fc receptor TRIM21. eLife, 7, e32660. (doi: 10.7554/eLife.32660)

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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.

Item Type:Articles
Additional Information:This work was funded by the Medical Research Council (UK; U105181010 and U105178934) and a Wellcome Trust Investigator Award. We thank Dr. Jonathan Pruneda for assistance with E2 discharge assays. CFD was supported by an NHMRC Early Career Fellowship (APP1110116).
Glasgow Author(s) Enlighten ID:Fletcher, Dr Adam
Authors: Dickson, C., Fletcher, A. J., Vaysburd, M., Yang, J.-C., Mallery, D. L., Zeng, J., Johnson, C. M., McLaughlin, S. H., Skehel, M., Maslen, S., Cruickshank, J., Huguenin-Dezot, N., Chin, J. W., Neuhaus, D., and James, L. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN (Online):2050-084X
Published Online:18 April 2018
Copyright Holders:Copyright © 2018, Dickson et al.
First Published:First published in eLife 7:e32660
Publisher Policy:Reproduced under a Creative Commons Licence

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