University of Dundee

Dr. Yogesh Kulathu

Ubiquitin signalling mechanisms
Position: 
Programme Leader
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 388613, int ext 88613
Email: 

Research

The research goal of my lab is to understand how cellular signal transduction is regulated by the combined influences of ubiquitylation and phosphorylation. We are interested in discovering biological roles of different ubiquitin modifications and studying how cross talk between various posttranslational modifications regulates cellular signalling.  The lab aims to characterize the structural and mechanistic principles underlying allosteric regulation of enzymes by ubiquitylation.

Ubiquitin, a 76 amino acid protein can be covalently attached to substrate proteins by an enzymatic cascade of three different classes of enzymes, namely ubiquitin activating enzymes E1, ubiquitin conjugating enzymes E2 and ubiquitin ligases E3. Protein ubiquitylation can result in substrates being modified with a single ubiquitin, termed monoubiquitylation. Alternatively the seven lysines (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, Lys63) or the amino terminal methionine (Met1) within ubiquitin can themselves be sites of ubiquitin conjugation to result in the formation of ubiquitin chains. As a result, polyubiquitin chains of eight different linkage types having different topologies can be assembled.

Early work in the 1970s showed that proteins are ubiquitylated with Lys48-linked chains prior to their recognition and degradation by the proteasome. Ubiquitin mediated protein degradation plays a crucial part in many cellular processes such as cell growth, cell-cycle regulation, cellular stress responses, etc. More recently, non-proteolytic roles for ubiquitylation have been uncovered in several processes including cytokine receptor signalling, endocytosis, histone modification and kinase activation. These efforts have been focused largely on two linkage types – Lys63 and Met1 (linear), and very little is known about biological roles for the other five linkages. We now appreciate that ubiquitin chains of different linkage types adopt distinct conformations and to achieve linkage-specific polyubiquitin recognition, binding proteins exploit these structural differences. However, many of these linkage-specific binding proteins or readers of the modification remain to be discovered.

Research on uncovering roles for these unstudied linkages has been hampered largely by a limitation in the availability of tools to probe the ubiquitin system. Further, enzymes that regulate ubiquitylation and substrates that get ubiquitylated are poorly characterized. Deubiquitinases (DUBs) that reverse ubiquitylation are key regulators of the ubiquitin system and how these enzymes are recruited to specific ubiquitylated substrates and how DUB activity is modulated is also an area yet to be explored.

We are particularly interested in uncovering ubiquitin-dependent signalling nodes in lymphocytes where the roles for ubiquitylation in adaptive immune responses are poorly characterized. We also aim to study how signalling enzymes are modulated allosterically by ubiquitylation. Mechanistic understanding of how PTMs allosterically regulate kinases and DUBs is a long-term research goal of my lab.

The lab employs a multidisciplinary approach to dissect ubiquitin mediated signalling mechanisms. We use X-ray crystallography combined with biophysical and biochemical methods to understand the underlying molecular basis. We also employ transgenic mouse models and genetic approaches to complement our mechanistic studies.

Given the central roles that ubiquitylation plays in diverse cellular processes, it is not surprising that components of the ubiquitin system are exploited by infecting pathogens. Moreover dysfunction of the ubiquitin machinery is a contributing factor to cancer, inflammation due to malfunctioning immune cells and neurodegenerative disorders. Ultimately, a better understanding of the ubiquitin system will enable us to manipulate it and exploit components as targets for drug discovery.

Publications

Top 10 Publications

Kulathu Y, Akutsu M, Bremm A, Hoffmann K, Komander D. (2009).
Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain.
Nat. Struct. Mol. Biol. 16 1328-1330

Kulathu Y, Garcia FJ, Mevissen TET, Busch M, Arnaudo N, Carroll KS, Barford D, Komander D. (2013)
Regulation of A20 and other OTU deubiquitinases by reversible oxidation
Nat Commun 4, 1569

Kulathu Y, Komander D. (2012).
Atypical ubiquitylation — the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages
Nat Rev Mol Cell Biol 13, 508-523

Ekkebus R*, van Kasteren SI*, Kulathu Y, Scholten A, Berlin I, Geurink PP, de Jong A, Goerdayal S, Neefjes J, Heck AJ, Komander S, Ovaa H. (2013)
On terminal alkynes that can react with active-site cysteine nucleophiles in proteases
J Am Chem Soc. 135, 2867-2870.

Mevissen TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F, Freund SM, Ovaa H, Komander D. (2013)
OTU Deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis
Cell 154, 169-184

Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB, Kulathu Y, Wauer T, Hospenthal MK, Gyrd-Hansen M, Krappmann D, Hofmann K, Komander D. (2013)
OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin
Cell 153, 1312-1326

Kulathu Y, Hobeika E, Turchinovich G, Reth M. (2008).
The kinase Syk as an adaptor controlling sustained calcium signaling and B-cell development
Embo J. 27, 1333-1344.

Wossning T, Herzog S, Kohler F, Meixlsperger S, Kulathu Y, Mittler G, Abe A, Fuchs U, Borkhardt A, and Jumaa H. (2006).
Deregulated Syk inhibits differentiation and induces growth factor-independent proliferation of pre-B cells
J Exp Med. 203, 2829-2840.

Kohler F, Storch B*, Kulathu Y*, Herzog S*, Kuppig S, Reth M and Jumaa H. (2005).
A leucine zipper in the N terminus confers membrane association to SLP-65
Nature Immunol. 6, 204-210.

Kulathu Y, Grothe G, Reth M. (2009).
Autoinhibition and adaptor function of Syk
Immunol Rev. 232, 286-99.

Impact

Commercial Impact:

In collaboration with the pharmaceutical industry via the Division of Signal Transduction Therapy collaboration with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, Merck Serono and Pfizer the research ouptuts from my group contribute to accelerating the development of company drug development programmes through access to research data and reagents. Reagents are also commercialised to provide access to the wider scientific community via license arrangements with companies such as Millipore, AbCam and Ubiquigent.