Reorganization and disruption of the human proteome: pathogenesis and therapy
We are investigating the stability of human proteome during tumor progression, infection, neurodegeneration and aging. We aim to understand how the mammalian cell architecture is sustained under acute and chronic stress, such as nutrient deficiency, acidosis or oxidative damage. Mechanistically, we focus on three areas:
1. Reorganization of membrane-bound organelles during proteostasis stress.
2. Stress compartmentalization without membranes (RNA-protein assemblies).
3. Targeted disruption of human flavoproteome.
In 2011, we introduced a new paradigm to explain the toxicity of cellular amyloid. We demonstrated that aggregation results in numerous aberrant protein-protein interactions. Coaggregation of a substantial number of proteins with diverse functions inevitably leads to multifocal deficits and the collapse of the cellular protein network. Recently, we extended this paradigm to include aberrant protein-RNA interactions.
Olzscha H., Schermann S.M., Wörner A., Pinkert S., Hecht M.H., Tartaglia G.G., Vendruscolo M., Hayer-Hartl M., Hartl F.U., Vabulas R.M. (2011) Amyloid-like Aggregation Targets Metastable Proteins with Essential Functions. Cell. 144(1):67-78.
Alriquet M., Calloni G., Martínez-Limón A., Delli Ponti R., Hanspach G., Hengesbach M., Tartaglia G.G., Vabulas R.M. (2018) TRMT6/61A methyltransferase safeguards free mRNAs during proteostasis stress and amyloidogenesis. (Under revision)
In search of novel therapeutic strategies to prevent (infection, neurodegeneration, aging) or enhance (tumor therapy) this cellular break-down, we have committed to understand the molecular details of the destruction of macromolecular complexes. To this end, we use cell biological, biochemical and biophysical techniques; to identify and access relevant biological material for these investigations we are creating molecular chaperone-BAC-modified transgenic mice strains. In 2016, we established a mass spectrometry platform at the BMLS Institute and have been in charge of its maintenance and operation.