Emphases
Every protein that is synthesized needs to be disposed at some point of its life. This is mainly achieved by the ubiquitin-proteasome system, which degrades about 90% of all cellular proteins into small peptides. For degradation, proteins are first tagged with poly-ubiquitin chains and targeted for destruction by the 26S proteasome. Upon binding of the protein substrate to the proteasome, ubiquitin is recycled, the protein is unfolded, and degraded into small peptide fragments. These peptides are either used for recycling of amino acids or used as a communication system to define the cellular “self” towards the immune system via MHC class I presentation. Proper proteasome function is thus essential for numerous cellular processes such as protein turnover and quality control, cell growth and cell signaling, antigen presentation and immune response.
Our lab investigates the role of proteasomal protein degradation in chronic lung diseases. Watch our science slam on proteasome function in response to cigarette smoke on YouTube!
Proteasome Function in Lung Disease
There is accumulating evidence for a central role of proteasome function in chronic lung disease: on the one hand, the proteasome is a feasible target for therapeutic intervention in lung disease. On the other hand, alterations of proteasome function in the lung emerge as a new pathomechanism for chronic lung diseases. As the proteasome plays a key role in the regulation of growth factor signaling and protein quality control, its proper function is essential for maintaining lung function. Recent evidence suggests deregulation of proteasome expression and activity in chronic lung diseases.
Challenges for the Proteaseome
A particular challenge for proteasome function is the accumulation of protein damage in lung cells due to cigarette smoke exposure. The more than 4000 highly reactive chemicals in cigarette smoke have deleterious effects on the structure and function of proteins within the cell. Very similar, protein damage accumulates over time while the organism ages. These damaged and functionally impaired proteins are constantly disposed by the ubiquitin-proteasome system as part of the cellular protein quality control pathway. Upon degradation of proteins, small protein fragments are generated that are presented to the immune systems on the cell surface as a kind of barcode. Thus, the immune system obtains the latest information on the cell’s current state of health. Consequently, the proteasome also has a major communication function for the cell with its environment.
Effects of Proteasome Impairment
Impairment of proteasome function, e.g. by cigarette smoke induced protein damage or aging, has deleterious consequences: First of all, damaged proteins accumulate and form proteotoxic aggregates in the cell. Moreover, controlled degradation of signal regulators is impaired which contributes to altered cell growth and transcriptional responses. Cellular stress is thus exaggerated. In addition, impaired proteasome function might be communicated to the immune system when generation of antigenic peptides is affected. In such a scenario, the proteasome no longer restricts cellular stress by degrading damaged proteins but rather amplifies it within the cell and expands the stress to the surrounding tissue.
Research Interests
Our research group investigates the expression and activity of the proteasome in conditions of chronic lung disease. For the comprehensive analysis of proteasome expression and function, we use cell culture and animal models and also patient’s samples. We are also investigating how cigarette smoke alters the structure of the proteasome and how this will affect proteasome function. Another project analyses how this impairment in proteasome function by cigarette smoke is being imparted to the immune system. The essential role of the proteasome for timely and controlled degradation of cellular proteins also makes it an attractive target for the therapy of chronic lung diseases such as lung cancer and pulmonary fibrosis. We are investigating the effects of lung specific proteasome inhibition as a putative therapeutic approach for lung tumors and fibrosis using cell culture and animal models.