John Christianson

Monday, 29 October 2018 | 12:00 noon

Nuffield Dept. of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research CentreUniversity of Oxford, UK

Beyond ERAD: emerging roles for ubiquitin ligase complexes of the endoplasmic reticulum

(Host: O. Burrone)

The eukaryotic endoplasmic reticulum (ER) is the entry portal for more than 30% of the human proteome, maturing and deploying a broad collection of protein topologies from this organelle. Polypeptides that misfold during biogenesis are degraded through the ubiquitin-proteasome dependent process of ER-associated degradation (ERAD), preventing their build up and aggregation as part of the ER quality control mechanisms that preclude ER stress and cell death. ERAD is principally mediated by a multi-subunit complex assembled around the membrane-embedded ubiquitin ligase Hrd1.

The Hrd1 complex employs specialised cofactors to help recognise, retrotranslocate and ubiquitinate aberrant secretory cargo, thus clearing it from the ER. Work from our group and others has defined Hrd1 complex constituency and determined the functional contribution of individual cofactors to ERAD and ER stress resolution.

Along with Hrd1, there are more than 25 other ubiquitin ligase (E3) embedded in the ER membrane whose roles are less well defined. We have developed a comparative proteomic pipeline to define the cofactors assembling with each E3 in an effort to understand their individual organisation and contributions to cellular homeostasis. While providing additional insight into ERAD mediated by Hrd1, we also uncovered key roles in the Wnt signalling pathway, innate immune signalling and calcium homeostasis for other E3 complexes. Our data indicate a rich diversity of function within ER-resident E3s complexes with important contributions beyond just ER quality control.