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Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling.
Elife. 2020 07 02; 9E

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 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.

Authors+Show Affiliations

Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford, United Kingdom.TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford, United Kingdom.TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford, United Kingdom.Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32614325

Citation

Fenech, Emma J., et al. "Interaction Mapping of Endoplasmic Reticulum Ubiquitin Ligases Identifies Modulators of Innate Immune Signalling." ELife, vol. 9, 2020.
Fenech EJ, Lari F, Charles PD, et al. Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling. Elife. 2020;9.
Fenech, E. J., Lari, F., Charles, P. D., Fischer, R., Laétitia-Thézénas, M., Bagola, K., Paton, A. W., Paton, J. C., Gyrd-Hansen, M., Kessler, B. M., & Christianson, J. C. (2020). Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling. ELife, 9. https://doi.org/10.7554/eLife.57306
Fenech EJ, et al. Interaction Mapping of Endoplasmic Reticulum Ubiquitin Ligases Identifies Modulators of Innate Immune Signalling. Elife. 2020 07 2;9 PubMed PMID: 32614325.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling. AU - Fenech,Emma J, AU - Lari,Federica, AU - Charles,Philip D, AU - Fischer,Roman, AU - Laétitia-Thézénas,Marie, AU - Bagola,Katrin, AU - Paton,Adrienne W, AU - Paton,James C, AU - Gyrd-Hansen,Mads, AU - Kessler,Benedikt M, AU - Christianson,John C, Y1 - 2020/07/02/ PY - 2020/03/26/received PY - 2020/06/11/accepted PY - 2020/7/3/entrez PY - 2020/7/3/pubmed PY - 2020/7/3/medline KW - RNF26 KW - STING KW - cell biology KW - endoplasmic reticulum KW - immunology KW - inflammation KW - innate immune response KW - none KW - ubiquitin ligase JF - eLife JO - Elife VL - 9 N2 - 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. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/32614325/Interaction_mapping_of_endoplasmic_reticulum_ubiquitin_ligases_identifies_modulators_of_innate_immune_signalling L2 - https://doi.org/10.7554/eLife.57306 DB - PRIME DP - Unbound Medicine ER -
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