Format

Send to

Choose Destination

Links from Structure

Elife. 2018 Apr 18;7. pii: e32660. doi: 10.7554/eLife.32660.

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

Author information

1
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
#
Contributed equally

Abstract

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.

KEYWORDS:

Antibodies; E. coli; Fc receptors; Virology; human; molecular biophysics; structural biology

PMID:
29667579
PMCID:
PMC5906095
DOI:
10.7554/eLife.32660
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center