Regulation of protein degradation and homeostasis by ubiquitylation
Lead Research Organisation:
University of Dundee
Department Name: UNLISTED
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.
People |
ORCID iD |
Publications
Abdul Rehman SA
(2021)
Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2.
in Molecular cell
Gorka M
(2022)
Chemical biology tools to study Deubiquitinases and Ubl proteases.
in Seminars in cell & developmental biology
Kelsall IR
(2019)
Coupled monoubiquitylation of the co-E3 ligase DCNL1 by Ariadne-RBR E3 ubiquitin ligases promotes cullin-RING ligase complex remodeling.
in The Journal of biological chemistry
Kulathu Y
(2019)
Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach.
in Biological chemistry
Kwasna D
(2018)
Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability.
in Molecular cell
Lange SM
(2022)
Purification, crystallization and drug screening of the IRAK pseudokinases.
in Methods in enzymology
Lange SM
(2021)
Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allosteric Mechanism for Negative Regulation.
in Structure (London, England : 1993)
Lange SM
(2021)
Linking K29-Ub chains to biology.
in Nature chemical biology
Lange SM
(2022)
Deubiquitinases: From mechanisms to their inhibition by small molecules.
in Molecular cell
Millrine D
(2022)
Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation.
in Cell reports
Millrine D
(2023)
A guide to UFMylation, an emerging posttranslational modification.
in The FEBS journal
Peter JJ
(2022)
A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation.
in The EMBO journal
Related Projects
| Project Reference | Relationship | Related To | Start | End | Award Value |
|---|---|---|---|---|---|
| MC_UU_00018/1 | 01/04/2018 | 31/03/2024 | £4,394,000 | ||
| MC_UU_00018/2 | Transfer | MC_UU_00018/1 | 01/04/2018 | 31/03/2024 | £2,542,000 |
| MC_UU_00018/3 | Transfer | MC_UU_00018/2 | 01/04/2018 | 31/03/2024 | £3,121,000 |
| MC_UU_00018/4 | Transfer | MC_UU_00018/3 | 01/04/2018 | 31/03/2024 | £2,751,000 |
| MC_UU_00018/5 | Transfer | MC_UU_00018/4 | 01/04/2018 | 31/03/2024 | £3,744,000 |
| MC_UU_00018/6 | Transfer | MC_UU_00018/5 | 01/04/2018 | 31/03/2024 | £2,520,000 |
| MC_UU_00018/7 | Transfer | MC_UU_00018/6 | 01/04/2018 | 31/03/2024 | £2,557,000 |
| MC_UU_00018/8 | Transfer | MC_UU_00018/7 | 01/04/2018 | 31/03/2024 | £2,128,000 |
| Description | (UBIMOTIF) - Short linear interaction motifs as specificity determinants in the ubiquitin system - discovery, mechanisms and therapeutic opportunities |
| Amount | € 4,147,222 (EUR) |
| Funding ID | 860517 |
| Organisation | European Commission |
| Sector | Public |
| Country | European Union (EU) |
| Start | 12/2019 |
| End | 11/2023 |
| Description | Defining mechanisms and function of protein UFMylation |
| Amount | £657,309 (GBP) |
| Funding ID | BB/T008172/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2020 |
| End | 01/2023 |
| Description | ERC Consolidator Grant 2020 |
| Amount | € 2,185,859 (EUR) |
| Funding ID | ERC-2020-COG-101002428 |
| Organisation | European Research Council (ERC) |
| Sector | Public |
| Country | Belgium |
| Start | 01/2022 |
| End | 12/2026 |
| Description | Tenovus COVID grants |
| Amount | £20,000 (GBP) |
| Organisation | Tenovus Cancer Care |
| Department | Tenovus Scotland |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 07/2020 |
| End | 12/2020 |
| Description | Towards a molecular understanding of Myddosome organization and regulation of IRAK kinase activity |
| Amount | £803,612 (GBP) |
| Funding ID | BB/W007401/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2023 |
| End | 12/2025 |
| 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 | Cov2 research |
| Organisation | Goethe University Frankfurt |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | We developed nanobodies that could inhibit the protease activity of Nsp3 |
| Collaborator Contribution | Partners tested these nanobodies in viral replication assays |
| Impact | Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies. Armstrong LA, Lange SM, Dee Cesare V, Matthews SP, Nirujogi RS, Cole I, Hope A, Cunningham F, Toth R, Mukherjee R, Bojkova D, Gruber F, Gray D, Wyatt PG, Cinatl J, Dikic I, Davies P, Kulathu Y. PLoS One. 2021 Jul 16;16(7):e0253364. doi: 10.1371/journal.pone.0253364. eCollection 2021. PMID: 34270554 |
| Start Year | 2020 |
| 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 | EM collaboration |
| Organisation | University of Leeds |
| Department | Astbury Biostructure Laboratory |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We work together to determine cryo-EM structures of the complexes we are studying |
| Collaborator Contribution | We work together to determine cryo-EM structures of the complexes we are studying |
| Impact | Not yet |
| Start Year | 2020 |
| Description | SLIMs in DUB substrate recognition |
| Organisation | Uppsala University |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | In this collaboration we are working together to define short linear motifs recognized by Deubiquitinases. |
| Collaborator Contribution | In this collaboration we are working to define short linear motifs recognized by Deubiquitinases. Our partners have a phage display system that we have been using to screen DUBs for binding motifs |
| Impact | Not yet |
| Start Year | 2020 |
| Description | Bright Club Aberdeen at Explorathon 2019 |
| 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 | Explorathon is a pan-Scotland series of public engagement events ran as part of European Researchers Night, itself an initiative of the European Commission. As part of their programme, the University of Aberdeen Public Engagement with Research Unit (PERU) organised a Bright Club-style event at a local comedy venue in Aberdeen, inviting one of our lab members (who has previously worked with PERU at other Bright Club Aberdeen nights) to participate as a performer. Feedback was very positive, with an invitation from the owner of the venue to the participants to take part in one of their regular open mic nights. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.explorathon.co.uk/events/bright-club-aberdeen/ |
| Description | Bright Club Dundee #32 |
| 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 | Bright Club was initially developed at UCL in 2009 as part of an experiment to fuse stand-up comedy with public engagement. This was deemed a resounding success and the format has since been exported to multiple cities across the UK and Ireland. The Dundee event has been running since 2011 and involves researchers preparing a short stand-up comedy routine based on an aspect of their work, or their experiences as a researcher. These presentations are then delivered to an audience comprised of the general public, with support from a professional comedian or entertainer who acts as compère. A member of our group represented the lab as one of the performers, and feedback from the audience was overwhelmingly positive. The researcher in question was invited back to participate in a further University of Dundee comedy club event later in the year. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.brightclubdundee.org/2019/04/30/bright-club-dundee-32-line-ups-and-tickets/ |
| Description | Festival of the Future Comedy Club |
| 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 | The annual Festival of the Future comprises a week-long series of events ran by the University of Dundee celebrating science, arts and culture. As part of this a comedy club event was staged with support from comedian Phill Jupitus. This was similar in nature to other Bright Club style events, with a group of researchers from the University deliver stand-up comedy routines to the general public based on their research. Following their appearance at a similar event earlier in the year, one of our lab members was invited to perform a set, again receiving positive feedback from audience members. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.dundee.ac.uk/festival-future/programme/2019/fri-comedy-club-with-phill-jupitus.php |
| 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 |