Dr. Yogesh Kulathu
Yogesh graduated with a Bachelor’s degree in Chemical Engineering in 2000 from Birla Institute of Technology and Science (BITS), Pilani, India. He then went on to do a PhD in Immunology at the Max Planck Institute of Immunobiology and University of Freiburg in Germany, where he worked on B cell antigen receptor signalling and protein tyrosine kinase regulation. To apply structural biology methods to study cell signalling, Yogesh moved to Cambridge in 2009 to work at the MRC Laboratory of Molecular Biology. He was awarded a Marie Curie Intra-European Fellowship and an EMBO Long term fellowship to work on the structural basis driving linkage specificity in ubiquitin binding domains and in the ovarian tumour (OTU) family of deubiquitinases. In February 2013, Yogesh relocated to the MRC PPU to establish his research program, focussing on ubiquitin signalling mechanisms. In 2015 Yogesh received a prestigious ERC Starting Grant, and was selected as a EMBO Young Investigator. Yogesh is a recipient of the Lister Prize from the Lister Institute of Preventive Medicine.
Ubiquitin signalling mechanisms
An important role for the ubiquitin system is in the quality control and degradation of misfolded and damaged proteins, a process central to maintaining proteostasis. Ubiquitylation also has important non-degradative roles in signalling pathways. One of the ways ubiquitylation is able to mediate such a diverse array of functions is because a range of different ubiquitin signals can be formed. How does the cellular machinery distinguish between different ubiquitin signals to orchestrate a specific response? And what regulatory mechanisms ensure that ubiquitin signals are tightly regulated?
Our lab is interested in understanding (i) how ubiquitin and ubiquitin-like modifiers modulate protein degradation and proteostasis, and (ii) how ubiquitin signalling regulates T-lymphocyte biology and immune responses. To address these fundamental questions, we combine structural, biochemical and genetic approaches to uncover and understand the underlying pathways and mechanisms.
Our research has provided insights into the assembly and recognition of different ubiquitin signals. We recently discovered novel regulators of protein degradation that are highly conserved in evolution. Failure to degrade proteins in a timely manner is the underlying cause of diseases such as cancer and neurodegeneration. By studying how ubiquitylation regulates protein degradation and proteostasis we hope to better understand the molecular causes of disease that we can exploit for the development of effective therapeutic strategies.
Selected Recent Publications
Dominika Kwasna, Syed Arif Abdul Rehman, Jayaprakash Natarajan, Stephen Matthews, Ross Madden, Virginia De Cesare, Simone Weidlich, Satpal Virdee, Ivan Ahel, Ian Gibbs-Seymour, Yogesh Kulathu (2018) Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability Mol Cell. 70(1) 150-164.e6
Kristariyanto, Y. A., Abdul Rehman, S. A., Weidlich, S., Knebel, A. and Kulathu, Y. (2017) A single MIU motif of MINDY-1 recognizes K48-linked polyubiquitin chains. EMBO Rep 18 392-402
Leznicki P and Kulathu Y. (2017) Mechanisms of regulation and diversification of Deubiquitylating enzyme function J Cell Sci doi:10 1242/jcs.201855
Abdul Rehman, S. A., Kristariyanto, Y. A., Choi, S. Y., Nkosi, P. J., Weidlich, S., Labib, K., Hofmann, K. and Kulathu, Y. (2016) MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes. Mol Cell 63 146-55
Kristariyanto, Y. A., Abdul Rehman, S. A., Campbell, D. G., Morrice, N. A., Johnson, C., Toth, R., Kulathu, Y. (2015) K29-selective ubiquitin binding domain reveals structural basis of specificity and heterotypic nature of k29 polyubiquitin Mol Cell 58 83-94
Kristariyanto, Y. A., Choi, S. Y., Rehman, S. A., Ritorto, M. S., Campbell, D. G., Morrice, N. A., Toth, R., Kulathu, Y. (2015) Assembly and structure of Lys33-linked polyubiquitin reveals distinct conformations Biochem J 467 345-352
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.