Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling
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Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling. / Fenech, Emma J; Lari, Federica; Charles, Philip D; Fischer, Roman; Laétitia-Thézénas, Marie; Bagola, Katrin; Paton, Adrienne W; Paton, James C; Gyrd-Hansen, Mads; Kessler, Benedikt M; Christianson, John C.
In: eLife, Vol. 9, 02.07.2020.Research output: Contribution to journal › Journal article › Research › peer-review
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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
N1 - © 2020, Fenech et al.
PY - 2020/7/2
Y1 - 2020/7/2
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.
AB - 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.
KW - Endoplasmic Reticulum/metabolism
KW - Immunity, Innate
KW - Protein Interaction Mapping
KW - Protein Interaction Maps
KW - Proteomics
KW - Signal Transduction
KW - Ubiquitin-Protein Ligases/metabolism
U2 - 10.7554/eLife.57306
DO - 10.7554/eLife.57306
M3 - Journal article
C2 - 32614325
VL - 9
JO - eLife
JF - eLife
SN - 2050-084X
ER -
ID: 280715983