Regulation of protein degradation and homeostasis by ubiquitylation

Lead Research Organisation: University of Dundee

Abstract

The majority of cellular functions are performed by proteins, making it vital to a cell to maintain functional proteins and destroy damaged ones, a process known as proteostasis. There is a progressive decline in proteostasis during the ageing process that results in the accumulation of damaged proteins. Loss of proteostasis and accumulation of misfolded and aggregated proteins is a common contributing factor to age-related diseases such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS). Damaged proteins need to be tagged with a destruction signal called ubiquitin. The ubiquitin signals are recognized by the proteasome, a large molecular machine which unfolds and degrades the damaged proteins. Ubiquitin signals are removed by a family of enzymes called deubuiquitinating enzymes (DUBs) and in line with this important regulatory function, mutated DUBs are implicated in several human diseases. The main goals of our research are to understand how ubiquitin signals target proteins for degradation, and how protein degradation is regulated by DUBs. I anticipate that our research will provide important insights into how proteostasis is regulated. An improved understanding of this fundamental process will form the basis for the development of novel strategies to combat neurodegenerative disorders

Technical Summary

Ubiquitylation is a versatile posttranslational modification that drives virtually every cellular process. An important role of ubiquitylation is in the quality control and degradation of misfolded and damaged proteins, a process central to maintaining a functional proteome or proteostasis. In addition, the ubiquitin proteasome system also mediates the degradation of signalling proteins that regulate cellular processes such as cytokine receptor signalling and the cell cycle. Failure to degrade proteins in a timely manner is the underlying cause of diseases such as cancer and neurodegenerative diseases that afflict millions of people worldwide. Hence, studying how ubiquitylation regulates protein degradation to maintain protein homeostasis is important to not only understand the molecular causes of disease but also for the development of effective therapeutic strategies, and forms the main research goal of my lab. Specifically, we want to understand the molecular mechanisms underlying the decoding of different ubiquitin signals that determine whether a ubiquitin signal results in protein degradation. We are particularly interested in how deubiquitylases (DUBs) act in quality control pathways that negatively regulate protein degradation. We also aim to explore how DUBs can be exploited in novel therapeutic strategies.

Publications

10 25 50
 
Description Ubicode
Amount € 270,000 (EUR)
Funding ID Ubicode 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2018 
End 12/2021
 
Description Defining substrates and mechanisms of Zup1 in DNA damage response 
Organisation University of Oxford
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Working together with researchers at the Department of Biochemistry, University of Oxford we defined the roles of a newly discovered enzyme in the maintenance of genome stability
Collaborator Contribution Delineated roles for ZUP1 in the DNA damage response
Impact We published a manuscript Kwasna et al. 2018, Molecular Cell reporting the discovery of Zup1 as a novel class of Deubiquitinating enzyme important for maintaining genome stability.
Start Year 2016
 
Description MRC Festical of Medical Research Inside Out Science Open Day 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact MRC Festival of Medical Research Inside Out Science Open day involved researchers from the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) and MRC Doctoral Training Programme students (from the Schools of Life Sciences and Medicine at the University of Dundee). The MRC Festival aimed to inform, inspire and stimulate thinking about medical research. Our event was held within the School of Life Sciences and involved seven table top engagement activities, five ten-minute accessible science talks given by PhD students and early career researchers, three lab tours and three videos about the scientific work of the Unit on loop with visitors. There were two new activities called Chromatography and Stem Cell Game trialled that were developed by MRC PPU staff and students plus previously developed activities. Prior to the open day event, a primary six class at Glebelands Primary School attended a 90 minute session to give valuable feedback on talks and new activities.

Members from my lab who participated were;
Marjorie Petitjean - Post Doctoral Researcher

Overall, 129 members of public (generally family groups) were reached with 103 people visiting on the day, a further 24 Primary Six pupils and their two teachers who gave feedback on the new talks and activities ahead of the event.
The event met a number of the objectives and key messages from the 2018 - 2023 MRC Protein phosphorylation and ubiquitination Public Engagement and Communications Plan which were:

Communications Objectives
1) Generate interest in science as a career path for young people in Dundee to reveal opportunities and make science accessible.
2) Share the unit's research expertise with non-scientific communities to raise awareness of the importance of basic research in understanding health and disease.

Key Messages
1) Basic research is vital - before we can develop new medicines we first need to understand how the body works in health and disease.
2) MRC PPU is an outstanding environment to pursue phosphorylation or ubiquitylation research.
3) As scientists we value new ideas and are open to sharing our work with all who have an interest in it.

Feedback
The visitors to the event were a mixture of ages which included family groups (children under 16 years) and adults up to 70 years of age. Feedback indicated that they enjoyed themselves overall and said they would come to a similar event again. Highlights included a game developed on the topic of Stem Cells and the laboratory tours. Around a third of visitors polled had not attended a University of Dundee event before indicating we were reaching new audiences.
The talks in particular stimulated a number of questions from the audience such as:
• How long does it take for a cell to divide?
• What would happen if you lost all your amino acids?
• Is it only older people who get Parkinson's?
• What is it about not being obese that helps protect you from Alzheimer's?
• What does wildtype mean?

Participants reported having a positive experience, they all said they'd do it again and that they'd recommend a colleague take part too.
Year(s) Of Engagement Activity 2018