Proteasome Function in Chronic Lung Disease

Scientific Focus

Source: Helmhotz Zentrum München, ILBD/CPC

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!

 

 

Main projects

Proteasome Function in Lung Disease

Lung diseases are on the second rank worldwide with respect to morbidity and mortality. For most respiratory diseases no effective therapies exist. While the proteasome has been successfully evaluated as a novel target for therapeutic interventions in cancer, neurodegenerative, and cardiac disorders, there is a profound lack of knowledge on the regulation of proteasome activity in chronic and acute 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 over time. Recent evidence suggests deregulation of proteasome expression and activity in chronic lung diseases. 

A particular challenge for proteasome function is the accumulation of protein damage in lung cells due to environmental exposures such as cigarette smoke. 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 proteasome as part of the cellular protein quality control pathway. Impairment of proteasome function, e.g. by cigarette smoke induced protein damage or aging, thus 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. 

Our research group investigates the expression and activity of the proteasome at 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 the effects of lung specific and nanoparticle mediated proteasome inhibition as a putative therapeutic approach for lung tumors using cell culture and animal models.

Projects:

  1. Regulation of proteasome expression and function in normal, aged and chronically diseased lung http://www.ncbi.nlm.nih.gov/pubmed/25989070
  2. Regulation of proteasome regulators in lung biology and disease
  3. Effect of cigarette smoke on proteasome function and antigen presentation http://www.ncbi.nlm.nih.gov/pubmed/22962013
  4. Proteasome as a therapeutic target for lung disease:
    Inhalative application of proteasome inhibitors for therapeutic use in cell and mouse models of lung cancer and pulmonary fibrosis (http://www.m4.de/en/personalized-medicine/m4-projects/details/T14.html)
    Smart nanoparticle-based delivery for targeted delivery of proteasome inhibitors (http://www.nano-initiative-munich.de)  http://www.ncbi.nlm.nih.gov/pubmed/25703655

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