Protein deubiquitylation controls the degradation of mislocalised secretory and membrane proteins and regulates endoplasmic reticulum function

Speaker: dr Paweł Leźnicki (University of Manchester, Manchester, United Kingdom)

Talk: Protein deubiquitylation controls the degradation of mislocalised secretory and membrane proteins and regulates endoplasmic reticulum function

Time: 23th November 2018, 9:00 am

Venue: Intercollegiate Faculty of Biotechnology, Abrahama 58, hall 042

Paweł Leźnicki graduated with an MSc in Biotechnology from the Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Poland, in 2006. He then moved to Manchester, United Kingdom, to work on the mechanisms of post-translational delivery of tail-anchored membrane proteins to the endoplasmic reticulum. He received his PhD degree in Biochemistry in 2010. At that point his research interests shifted towards studying protein degradation mediated by the ubiquitin-proteasome system. He investigated this process and the function of deubiquitylating enzymes initially at the University of Manchester (2011-2013) and then at the MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, United Kingdom, a world-renowned centre for ubiquitylation-oriented research. In 2017 he moved back to Manchester to continue his work on the role of deubiquitylating enzymes in the regulation of intracellular processes.

The ubiquitin-proteasome system is the predominant degradative route for the disposal of defective and/or unwanted proteins in eukaryotic cells. Polypeptides destined for the proteasome-mediated degradation are most often initially marked by covalent conjugation of a small polypeptide, ubiquitin. Ubiquitin can form polymers (ubiquitin chains or polyubiquitin) linked via lysine residues or the N-terminus of a ubiquitin monomer, and the residue used to build such chains defines the functional outcome of protein ubiquitylation. Importantly, ubiquitylation can be reversed by the action of a group of enzymes collectively known as deubiquitylating enzymes (DUBs). By studying the quality control of membrane and secretory proteins destined to the endoplasmic reticulum (ER) we have identified several factors that control the steady-state levels of membrane and secretory proteins that fail to reach the ER. Such mislocalised proteins (MLPs) are routed towards degradation by the BAG6 complex but can be rescued by SGTA, a protein that stimulates MLP deubiquitylation. Further studies defined the molecular basis of these processes. Our subsequent work uncovered an isoform-specific function of a deubiquitylating enzyme, USP35, in apoptosis, lipid metabolism and ER stress. It also opened up new avenues for future work addressing the role of DUBs in controlling the function of intracellular organelles and pathways.