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Mapping the protein-protein interactions of ubiquitin ligases in the endoplasmic reticulum has revealed a new complex that modulates innate immune signalling.

The function of cellular proteins can be regulated by ubiquitination - the addition of one (or more) ubiquitin molecules to the target proteins facilitated by a ubiquitin ligase enzyme. Ubiquitin ligases often assemble with cofactors to form larger complexes, which helps them operate correctly. A number of ubiquitin ligases that regulate essential activities in the cell, including protein quality control, are integrated in the membrane of a large cellular compartment called the endoplasmic reticulum (ER). Based on sequence analysis and previous reports, at least 25 ubiquitin ligases are predicted to be ER-localised but for most, how they are organised and their function is unknown.

In this paper published in published in the journal eLife, Dr Emma Fenech and colleagues from John Christianson’s lab when it was based at Ludwig Oxford collaborated with the Kessler group (Target Discovery Institute) and the Gyrd-Hansen group (Ludwig Oxford) to map over 450 protein-protein interactions for 21 of these predicted ER ubiquitin ligases. These numerous interactions reflect the diversity of the metabolic and homeostatic processes that these ER ubiquitin ligases are involved in.

As part of their analysis, the researchers discovered that RNF26 forms a complex with four other proteins to modulate innate immune signalling through the cGAS-STING pathway, which responds to the presence of ‘foreign’ or mislocalised DNA within cells. By mapping the interactions of the ER-resident ubiquitin ligases, Fenech et al have therefore created a resource for uncovering novel functions of these enzymes in different cellular processes, paving the way for future mechanistic studies to determine the tractability of ubiquitin ligases as potential therapeutic targets.