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Research projects

Overview

A fundamental principle of cells is their ability to maintain working biological systems in a changing environment. To do so, cells have developed safeguarding mechanisms that monitor the integrity and functionality of their proteome. Cellular surveillance systems sense dysfunction or damage of individual components and elicit adaptive stress responses to ensure cellular or organismal survival by orchestrating their repair, removal and replacement. Failure or deregulation of these protein homeostasis mechanisms is associated with aging as well as severe diseases including cancer, neurodegeneration and inflammatory disorders. We are aiming at a profound mechanistic understanding of protein homeostasis mechanisms controlling the integrity of cellular organelles.

Projects in the lab currently focus on three main aspects:

1.) Intramembrane proteolysis as the new regulatory arm of the ERAD pathway

About one third of all mammalian proteins are synthesized in the endoplasmic reticulum (ER), including important cellular proteins such as cell surface receptors and channels. The ER-associated degradation (ERAD) pathway is essentially important to remove misfolded and damaged proteins from the ER to maintain ER protein homeostasis. However, also native proteins can be targeted by ERAD, thereby controlling their abundance. The ERAD machinery forms several parallel pathways that allow recognition and dislocation of a heterogeneous spectrum of substrates. We and others showed that intramembrane proteases and catalytically inactive homologues, the so-called pseudoproteases, serve as central factors in ERAD controlling the abundance and activity of selected membrane proteins. In our lab, we use a combination of cell biology tools, biochemistry and proteomics to study the physiological function and the molecular mechanism of ER-resident proteases and pseudoproteases in protein homeostasis.

The ERAD pathway consists of several parallel degradation routes that are centered around E3 ubiquitin ligases and intramembrane proteases and pseudoproteases.
2.) Molecular mechanism of regulated protein secretion

Properly folded proteins are directed from the ER to the Golgi compartment via the so-called COPII-coated vesicles, which commonly depend on cargo receptors. We aim to resolve how the process of cargo selection is regulated at the ER exit sites. Moreover, the project group lead by Markus Plomann focuses on how cells control their secretome in response to stress. Normally, proteins destined for secretion or surface expression as plasma membrane proteins go through a well-studied Golgi complex for maturation. However, in recent years several alternative routes were identified, which either completely or partially bypass conventional secretory organelles. To characterize these mechanisms, we use the growth factor TGFβ1 as a model protein for unconventional secretion. Recently, we deciphered how cells reshape their extracellular proteome to adapt to multiple cellular stress stimuli, thus highlighting the biological role of unconventional protein secretion. Moreover, we revealed the signaling pathway that regulates this mode of secretion, thereby linking physiological stress signaling and nutrient sensing to the cellular stress response. With this characterization, we provide important mechanistic insights on the cell biology of unconventional protein secretion. Activity of this growth factor is essential for numerous processes during development, but misregulation of its activity leads to fibrosis and cancer.

Secretion of TGFβ1 requires the autophagic protein machinery to form carriers for efficient unconventional secretion. We could show that TGFβ1 represents one of these cargoes that requires the autophagic protein machinery for efficient secretion (Nüchel et al. 2018)
3.) Regulation of mitochondrial protein homeostasis

Mitochondria are highly dynamic organelles required for numerous essential metabolic processes. Mitochondrial dysfunction has severe cellular effects and has been linked to neurodegenerative disorders such as Parkinson’s disease. Several mutations in autosomal recessively inherited genes that lead to early onset Parkinson´s disease have been described. We initially discovered that the mitochondrial rhomboid protease PARL serves as a master regulator of the serine/threonine kinase PINK1 and its influence on mitophagy. More recently, we have become interested in the mechanism and function of the outer membrane dislocase Msp1 in yeast (known as ATAD1/Thorase in humans). In an unexpected twist, we found that Msp1 synergies with the ERAD E3 ubiquitin ligase Doa10 to control targeting fidelity of tail-anchored proteins to the outer mitochondrial membrane.

Fluorescent microscopy-based stability measurement of PINK1. Upon knockdown of PARL (right panel) fluorescent timer tag shifts from green color (sfGFP) to red (mCherry) demonstrating accumulation of PINK1 at the outer mitochondrial membrane. Subsequently the E3 ubiquitin ligase Parkin is recruited triggering removal of mitochondria by mitophagy (not shown).