ER Protein Quality Control: From Cellular Homeostasis to Therapeutic Vulnerability in Cancer

Host: Amos Liang

Venue: MSI Small Lecture Theatre, FLS

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.