Team Magdalena Paolino
Structural representation of ubiquitin, highlighting secondary structures and the residues of Lysine and Methionine (blue and yellow balls and sticks, respectively) that are used to form up to eight structurally different polyubiquitin chains; each with presumptive distinct cellular functions. Artwork: by Matias Machado, using VMD software.
Ubiquitination in health and disease.
Our research aims to unveil the diverse roles of ubiquitination in preventing or driving diseases. Ubiquitination is a posttranslational protein modification essentially required to maintain cellular homeostasis. Alterations in ubiquitin-dependent pathways have been implicated in the pathogenesis of several human diseases, including cancer, metabolic disorders, and alterations of the immune system. However, ubiquitination is a highly complex process and various aspects of the ubiquitin system are not yet fully understood. Gaining insight into the cellular and molecular mechanisms of ubiquitination, as well as into its physiological roles is therefore critical on the path to novel treatments. Our team applies innovative techniques to model diseases and alter the functions of ubiquitin-related genes, with the ultimate aim of revealing the underlying molecular mechanisms of disease pathogenesis that could be used for developing novel therapies.
Major research focus
Ubiquitination is a key post-translational modification widely used by cells to regulate and diversify protein functions. Ubiquitination refers to the process by which one, but often a chain of ubiquitin -a small 76-amino acid modifier- is covalently attached to a lysine residue within a substrate protein, by the enzymatic action of E3 ubiquitin ligases. The process is reversed by deubiquitinating enzymes, which hydrolyze ubiquitin linkages in order to maintain the ubiquitin balance. Although protein degradation was the first identified and, since then, the most characterized outcome of ubiquitination, we now know that ubiquitin is multifunctional and has also diverse non-proteolytic regulatory roles. The fate of the ubiquitinated protein depends on the length as well as the type of ubiquitin chain attached to the substrate. Depending on which residue within the ubiquitin molecule is used to form the ubiquitin-ubiquitin linkage, up to eight biochemically and structurally different polyubiquitin chains can be formed; each with presumptive distinct cellular functions. Despite this and other significant advances in our understanding of ubiquitination, key aspects of the process are still elusive. In particular, the biological importance of the less abundant types of ubiquitin chains as well as the pathophysiological roles of the deubiquitinating enzymes, have remained largely unexplored.
We want to address these important knowledge gaps by using a multidisciplinary approach that combines genetic, cellular, and molecular studies at the interface of basic and translational research. We utilize diverse in vitro, ex vivo and in vivo techniques to better understand the role of ubiquitin-related genes in the etiology of diseases, primarily focusing on cancer, immunity and metabolism. Our research aims to illuminate the complexity and dynamics of the ubiquitin code, uncover the molecular basis of these diseases, as well as provide novel opportunities to more specifically and effectively modulate ubiquitin-dependent pathways in the clinics.
Our research is supported by funds from the Karolinska Institutet, the Department of Medicine Solna, the Swedish Research Council, and the Ragnar Söderbergs Foundation.
Magdalena Paolino, Assistant Professor, Team leader
Anneli Olsson Laboratory Assistant
Azad Saei PhD, Associated
We are constantly looking for creative and highly motivated scientists to join the team. If you are interested, please send an email to email@example.com