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

Autor:	Fenech EJ; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Lari F; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Charles PD; TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford, United Kingdom., Fischer R; TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford, United Kingdom., Laétitia-Thézénas M; TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford, United Kingdom., Bagola K; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Paton AW; Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia., Paton JC; Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia., Gyrd-Hansen M; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Kessler BM; TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford, United Kingdom.; Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Christianson JC; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford, United Kingdom.; Oxford Centre for Translational Myeloma Research, University of Oxford, Botnar Research Centre, Oxford, United Kingdom.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Jul 02; Vol. 9. Date of Electronic Publication: 2020 Jul 02.
DOI:	10.7554/eLife.57306
Abstrakt:	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 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. Competing Interests: EF, FL, PC, RF, ML, KB, AP, JP, MG, BK, JC No competing interests declared (© 2020, Fenech et al.)
Databáze:	MEDLINE
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