Mar 19, 2020

Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling

bioRxiv
Emma J FenechJohn C Christianson

Abstract

Ubiquitin ligases (E3s) embedded in the endoplasmic reticulum (ER) membrane regulate essential cellular activities including protein quality control, calcium flux, and sterol homeostasis. At least 25 different, transmembrane domain (TMD)-containing E3s are predicted to be ER-localised, but for most their organisation and cellular roles remain poorly defined. Using a comparative proteomic workflow, we mapped over 450 protein-protein interactions for 21 different stably expressed, full-length E3s. Bioinformatic analysis linked ER-E3s and their interactors to multiple homeostatic, regulatory, and metabolic pathways. Among these were four membrane-embedded interactors of RNF26, a polytopic E3 whose abundance is auto-regulated by ubiquitin-proteasome dependent degradation. RNF26 co-assembles with TMEM43, ENDOD1, TMEM33 and TMED1 to form a complex capable of modulating innate immune signalling through the cGAS-STING pathway. This RNF26 complex represents a new modulatory axis of STING and innate immune signalling at the ER membrane. Collectively, these data reveal the broad scope of regulation and differential functionalities mediated by ER-E3s for both membrane-tethered and cytoplasmic processes.

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Mentioned in this Paper

Protein Expression
Cytoplasm
Bio-Informatics
Endoplasmic Reticulum, Membrane
Estrogen Receptor Positive
RNF26 protein, human
Calcium
Protein kinase modulator
Laptm5 protein, mouse
Immune Response-regulating Signaling Pathway

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