Project Details
Projekt
Chaperone-mediated redox control in organismal proteostasis regulation
Applicant
Professorin Dr. Kathrin Ulrich
Subject Area
Biochemistry
Cell Biology
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 531902955
As organisms age, the mechanisms responsible for protein quality control and the cellular response to protein unfolding stress deteriorate in individual cells, tissues, and organs. This decline contributes to the accumulation of aberrant proteins and the development of diseases. Additionally, the antioxidant defenses weaken, leading to an increase in reactive oxygen species. This imbalance can result in unspecific protein oxidation, which may cause proteins to unfold and aggregate and is linked to the onset and progression of various neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. A disrupted redox balance also directly impacts cellular ATP levels, which decrease upon oxidative stress. This reduction hampers the function of ATP-dependent systems, including chaperones and proteases, that are responsible for refolding or degrading misfolded and damaged proteins. In response to these conditions, cells activate ATP-independent chaperones that bind mis- and unfolded proteins to prevent widespread aggregation. We demonstrated that thiol oxidation of the highly conserved, dual-function protein ASNA-1 (Get3 in yeast) triggers the switch from its ATP-dependent targeting for tail-anchored membrane proteins into an ATP-independent chaperone. In this new role, ASNA-1 binds unfolding protein intermediates and facilitates their refolding or degradation. Preliminary work in C. elegans suggests that this function is vital for maintaining proteostasis and redox balance, thereby promoting healthy aging. To better understand ASNA-1’s tissue-specific functions and cell non-autonomous effects during age- and stress-dependent changes, we will manipulate its expression levels in individual tissues, such as the intestine, muscle, and neurons, and examine effects on motility, lifespan, and stress resistance. Through biochemical assays, we will study the functional switch of ASNA-1 into a molecular chaperone and investigate the tissue-specific impacts of a well-characterized, targeting-deficient mutant variant of ASNA-1. We will utilize quantitative proteomics to analyze protein aggregation following tissue-specific depletion of ASNA-1. Using genetically encoded fluorescent probes, we will monitor changes in the organismal redox balance and analyze the effects of ASNA-1 on proteostasis and redox homeostasis. We will further explore ASNA-1’s interactions with conserved longevity pathways and assess its potential role as a redox-regulated cargo receptor for mis- and unfolded proteins, which are cleared via autophagy and/or secretion in C. elegans and HeLa cells. Our aim is to dissect ASNA-1’s role as a redox-sensitive protein quality control factor in cell non-autonomous regulation of proteostasis and redox homeostasis, ensuring a functional and balanced proteome during environmental challenges, aging, and age-associated diseases.
DFG Programme
Research Units
