Investigating the essential roles of Ubiquitin-like molecules and the Ubiquitin Proteasome System

Dimitris Xirodimas

“The role of the ubiquitin-like molecule NEDD8 in the coordination between cell growth and cell cycle”

The ubiquitin-like molecule NEDD8

Post-translational modifications of proteins with ubiquitin and ubiquitin-like molecules (Ubls) such as SUMO and NEDD8 are critical mechanisms of protein function regulation. It is now believed that these pathways are involved in the control of almost every biological process in the cell, from protein destruction to regulation of transcriptional activity, subcellular localisation, DNA repair, endocytosis, signal transduction and autophagy. The pathways for protein conjugation with ubiquitin and Ubls are also major targets for therapeutic intervention. Inhibitors of the ubiquitin-proteasome pathway are used for the treatment of multiple myeloma and mantle cell lymphoma, whereas inhibitors of the NEDD8 pathway are in clinical trials. Our current research is focussed on the Ubl NEDD8, which has the highest homology and identity to ubiquitin amongst the family of Ubls. However, a distinct conjugation pathway exists that leads to the covalent conjugation of NEDD8 to substrate proteins. Genetic experiments in plants, S. pombe, Drosophila, C.elegans, and mice, have demonstrated a vital role for NEDD8 in cell growth, viability and development. However, compared to ubiquitination or SUMO conjugation much less is known about molecular targets and pathways controlled by NEDD8. The well-established role for NEDD8 is the regulation of the activity of cullin-based RING E3-ligases (CRLs) through modification of cullins. However, it is becoming evident that the NEDD8 proteome and regulated biological processes are more diverse than previously thought.

Our goal is to identify and characterize novel targets and functions for NEDD8 and mechanisms of regulation of NEDDylation.

Our current and future studies include:

  • Elucidation of the role of NEDD8 in the coordination between cell growth and cell cycle
  • Identification and characterisation of mechanisms of NEDD8 regulation
  • Establish genetic model systems (C.elegans) for nucleolar signalling

We are using biochemical, biological and proteomic approaches and recently developed genetic model systems (C.elegans) for components of the NEDD8 machinery.