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

Claire Dickson,Jingwei Zeng,James Cruickshank,Stephen H Mclaughlin,Christopher M Johnson,Leo C James,Adam J Fletcher,Sarah Maslen,Nicolas Huguenin-Dezot,Mark Skehel,Donna L Mallery,David Neuhaus,Jason W Chin,Ji-Chun Yang,Marina Vaysburd

doi:10.7554/elife.32660

Claire Dickson, Jingwei Zeng + Show 13 more

Open Access

https://doi.org/10.7554/elife.32660

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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.

Highlights

Antibodies are an essential component of protective immunity and their induction is a major aim of vaccination
Consistent with the NFkB result, while endogenous TRIM5a underwent rapid recycling we found little evidence of TRIM21 turnover even after several hours (Figure 1B and Figure 1—figure supplement 1)
Both mutants remained active and could catalyse unanchored K63 chain synthesis, Ube2W-primed anchored K63 chain extension and ubiquitin discharge (Figure 1G–I), albeit less efficiently than wild-type. These results demonstrate that a preformed TRIM21 RING dimer is not a pre-requisite for ubiquitination activity

Summary

Introduction

Antibodies are an essential component of protective immunity and their induction is a major aim of vaccination. FcR immune signalling is influenced at multiple levels by; varying cell type expression and abundance, balancing the activity of inhibitory vs activatory receptors, requiring receptor crosslinking, setting minimal activation thresholds and by synergising with other pattern recognition receptors (PRRs) (Vogelpoel et al, 2015). These diverse mechanisms, deciphered over many decades, operate individually and synergistically to precisely regulate extracellular antibody immunity (Bruhns and Jonsson, 2015)

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