2. Academic Validation
  3. Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling

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

  • Elife. 2020 Jul 2;9:e57306. doi: 10.7554/eLife.57306.
Emma J Fenech 1,  Federica Lari 1,  Philip D Charles 2,  Roman Fischer 2,  Marie Laétitia-Thézénas 2,  Katrin Bagola 1,  Adrienne W Paton 3,  James C Paton 3,  Mads Gyrd-Hansen 1,  Benedikt M Kessler 2 4,  John C Christianson 1 5 6
Affiliations

Affiliations

  • 1 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • 2 TDI Mass Spectrometry Laboratory, Target Discovery Institute, University of Oxford, Oxford, United Kingdom.
  • 3 Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
  • 4 Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • 5 Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford, United Kingdom.
  • 6 Oxford Centre for Translational Myeloma Research, University of Oxford, Botnar Research Centre, Oxford, United Kingdom.
PMID: 32614325 DOI: 10.7554/eLife.57306
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.

Keywords

RNF26; STING; cell biology; endoplasmic reticulum; immunology; inflammation; innate immune response; none; ubiquitin ligase.

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