Priority Research Area Chronic Lung Diseases

Immunology and Cell Biology

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Projects

Leibniz-Gemeinschaft "ImmunoPROteasomes in LUNG health and disease"

In this project, we explore the possibility that the inducible nature of the immunoproteasome is exploited by the cell to enable dynamic adaptation of 20S proteasome function as part of an evolutionary conserved immune and stress response. This concept proposes a broad role for the immunoproteasome in immune and stress signaling, which we will systematically explore. In particular, we aim to understand whether standard, immuno- and the various types of mixed proteasomes have distinct functions e.g. by localizing to distinct cell types or subcellular sites, degrading different substrates, or by interacting with defined proteasome regulators. Solving these questions is key for a detailed understanding of the function of immuno-proteasomes in health and disease. It will pave the way for validation of the immunoproteasome as a therapeutic target allowing specific inhibition of single or multiple immunoproteasome subunits in disease with novel specific immunoproteasome inhibitors that are currently being developed.

BMBF: TARGETING ALTERNATIVE PROTEASOME COMPLEXES FOR LUNG CANCER THERAPY

Lung cancer is a deadly disease with a median survival rate of only 5 years. Despite some progress in the treatment of lung tumors, new and innovative therapies are urgently needed. Current inhibitors of the proteasome, the main protein degradation system of the cell, block the activity of all proteasome complexes in all cells thereby causing broad cytotoxicity. Targeting of specific proteasome complexes provides selective inhibition and reduces unwanted side-effects. We here aim to target the alternative proteasome activator PA200. PA200 is upregulated in lung tumors correlating with worsened patient survival and suggesting a potential role in lung cancer progression. In this project, we investigate the cellular function of PA200 in lung cancer cells in detail to first validate it as a therapeutic target and then identify targeted inhibitory agents by high-throughput drug screening approaches. Selective PA200-inhibitory compounds will be validated in detail in cells, animal models and lung tumors from patients.

DFG/ANR: The role of the proteasome activator PA200 in myofibroblast differentiation and fibrosis of the lung

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no effective therapies beyond lung transplantation. The pathogenesis of IPF involves aberrant wound healing in response to continuous or repeated damage of the alveolar epithelium and subsequent activation of myofibroblasts. These activated myofibroblasts are key drivers for fibrosis as they produce excessive extracellular matrix proteins which deposition then contributes to impaired lung function and finally death in IPF patients. Dysregulation of the proteasome system – a central gatekeeper of protein homeostasis - is emerging as a novel pathomechanism for IPF. While application of catalytic proteasome inhibitors is hampered due to their toxic side effects, proteasome function might be modulated more specifically by interference with defined proteasome complexes. In this project, we explore the role and regulation of the alternative proteasome complexes containing the proteasome activator PA200, which we have previously identified as a negative regulator of myofibroblast differentiation (Welk et al., Scientific Reports 2019).