Abstract:

Proteins that fail to fold correctly in the endoplasmic reticulum (ER) are eliminated through ER-associated degradation (ERAD), a ubiquitin-proteasome-dependent quality-control pathway essential for maintaining organelle homeostasis. Central to this process is the ER membrane-embedded HRD1 ubiquitin ligase complex, which brings together the machinery for substrate recognition, ubiquitylation, and extraction to target aberrant proteins to proteasomes for degradation.

Our lab seeks to understand how the organisation and activity of the HRD1 complex enable efficient disposal of the diverse range of proteins that misfold during biogenesis in the ER. We investigate how HRD1 coordinates the assembly of its cofactors, how this organisation enables the successive steps of ERAD, and how key events such as substrate ubiquitylation take place in the unusual environment of the ER membrane.

The capacity of ERAD becomes especially important when cells experience sustained proteotoxic stress. Many cancers operate under conditions that place exceptional demands on the ER and survive by engaging adaptive branches of the unfolded protein response (UPR) that augment protein-folding and degradation capacity. This adaptation can create a form of “non-oncogenic addiction”, in which pathways that normally maintain cellular homeostasis become essential for cancer cell fitness.

This seminar will explore the molecular machinery and ubiquitylation mechanisms that underpin ERAD, show how these pathways support adaptation to proteotoxic stress, and ask whether their increased importance in cancer creates vulnerabilities that can be exploited therapeutically.

Bio:

John Christianson is Professor of Cell Biology in the Botnar Research Centre at the University of Oxford and a Cancer Research UK Senior Research Fellow. His laboratory studies the molecular mechanisms that maintain protein quality and homeostasis within the endoplasmic reticulum (ER), and how these systems enable cells to adapt to stress in health and disease.

His research has helped define the molecular machinery and functional networks that govern ER-associated degradation (ERAD), a ubiquitin-dependent protein quality control pathway responsible for recognising and eliminating misfolded proteins from the ER. His group combines proteomic, biochemical and cell biological approaches to understand how ER protein quality control, ubiquitination and membrane protein homeostasis contribute to cellular fitness. A major focus is understanding how cancer cells exploit these pathways to tolerate chronic proteotoxic stress, and whether dependencies within ER homeostasis can reveal new therapeutic vulnerabilities, particularly in multiple myeloma.

John received his PhD in Neurobiology from the University of Chicago and completed his postdoctoral training at Stanford University before establishing his laboratory at the Ludwig Institute for Cancer Research in Oxford. When not in the lab, he can often be found playing or coaching softball, homebrewing, or white-water kayaking.