Proteins are large, complex molecules that carry out the majority of functions in cells. Therefore, their correct regulation is paramount for the maintenance of healthy tissues and organs. Proteins are regulated by small chemical changes that are carried out by enzymes and result from the various environmental stimuli met by cells. These chemical changes, called post-translational modifications (PTMs), determine when, where and how proteins work and their deregulation can upset normal physiological function and contribute to the development of disease.
We focus on the PTM citrullination, which is found at abnormally high levels in pathologies such as Rheumatoid Arthritis, Multiple Sclerosis, Ulcerative Colitis and cancer, among others. We aim to understand how the enzymes that carry out citrullination are both regulated in normal physiology and deregulated in disease, in order to be able to target them therapeutically.
Citrullination (or deamination) is carried out by a small family of enzymes called peptidylarginine deiminases (PADIs) and is involved in innate immunity, nerve cell myelination, skin homeostasis and pluripotency. Conversely, abnormal citrullination is a pathological feature of diseases such as autoimmunity (rheumatoid arthritis, multiple sclerosis, ulcerative colitis, psoriasis), neurodegeneration (Alzheimer's and prion diseases), atherosclerosis and late stage cancer, while its inhibition by genetic and pharmacological means was shown to prevent or revert some of these pathologies. Despite the likely mechanistic importance of citrullination in both cell physiology and disease, it remains largely unexplored.
The central aims of our work are to define the molecular mechanisms that control PADI activation under physiological conditions, understand how PADIs modulate protein and cell function and decipher how abnormal citrullination contributes to pathology. We employ a combination of biochemical, genomic, molecular and cell biological approaches, as well as in vivo model systems, focusing on two of the main physiological systems where PADI function can be traced, namely inflammatory cells and pluripotent stem cells. We hope that this work will significantly advance our current understanding of citrullination and reveal new regulatory mechanisms involved in both physiology and disease.
- Prof Michael Lund Nielsen, University of Copenhagen, Denmark
- Prof Kamil Kranc, CRM, University of Edinburgh, UK
- Prof Adriano Rossi, Centre for Inflammation Research, University of Edinburgh, UK
- Dr José Luis Carcia Perez, MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, UK
- Dr Conçalo Castelo-Branco, Karolinska Institutet, Sweden