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

By Emma J Fenech, Federica Lari, Philip Charles, Roman Fischer, Marie Laétitia-Thézénas, Katrin Bagola, Adrianne W. Paton, James C. Paton, Mads Gyrd-Hansen, Benedikt M Kessler, John C Christianson

Posted 19 Mar 2020
bioRxiv DOI: 10.1101/2020.03.18.993998 (published DOI: 10.7554/eLife.57306)

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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