1. Research Background:
Cellular differentiation, developmental processes, and environmental factors challenge the integrity of the proteome in every eukaryotic cell. The maintenance of protein homeostasis, or proteostasis, involves the degradation of misfolded and damaged proteins, and is essential for cellular function, organismal growth, and ultimately viability. Sustaining proteostasis is not only a long-term challenge for individual cells but also for entire organisms, since damaged proteins accumulate with stress and aging. It is commonly thought that age-related impairment of proteostasis affects general quality control networks, causing enhanced aggregation of misfolded proteins that can be toxic for cells and shortens organismal lifespan. Not all tissues are equally susceptible to the toxicity of protein aggregates, suggesting tissue-specific differences in proteostasis pathways. In humans, aberrant protein aggregation is often associated with neurodegeneration in age-dependent disorders such as Alzheimer’s and Parkinson’s diseases.
The ubiquitin/proteasome system (UPS) is a major proteolytic route functioning in a cellular network that helps to maintain the proteome during stress and aging. Degradation of damaged proteins is mediated by the 26S proteasome upon attachment of ubiquitin proteins. Another proteolytic system supporting proteostasis is the autophagy-lysosome pathway that degrades proteins inside activated autophagosomes. An age-related impairment of either of these systems causes enhanced protein aggregation and affects lifespan, reflecting functional overlap and cooperation between UPS and autophagy in stress and aging. The ultimate goal of our research is to assemble a global picture of stress-induced proteolytic networks critical for aging. We address both cellular and organismal regulation of protein degradation pathways using the powerful genetic model of Caenorhabditis elegans.
2. Research questions addresses by the group:
Proteostasis is achieved via a conserved network of quality control pathways that support the generation of correctly folded proteins, prevent proteins from misfolding, and remove potentially harmful protein species. Unfortunately, the proteostasis network has a limited capacity and its impairment causes protein aggregation that deteriorates both cellular and organismal viability. Recent studies identified cell-nonautonomous regulation of proteotoxic stress response, suggesting the existence of intricately balanced proteostasis networks important for integration and maintenance of the organismal proteome. Our research particularly aims to understand the dynamic regulation of proteolytic pathways that integrate environmental and physiological changes. The detailed analysis of both cellular and tissue-related coordination of proteostasis will allow us to assemble a global picture of conserved protein degradation networks important to safeguard the organismal proteome in health and disease. Our lab aims to unravel the interplay between proteolytic networks at the molecular, cellular, and organismal level and to define adaptation mechanisms that ensure its integrity in response to environmental stress conditions or inherited, disease-associated mutations. The central research program is focused on the following points:
- Proteostasis mechanisms important for aging and age-related diseases
- Cell-autonomous regulation of protein quality control
- Interorgan communication in sensory perception and aging
- Pathomechanisms underlying disease-related dysfunction
3. Possible projects:
Keeping all proteins of an organism in balance is fundamental to life because it safeguards tissue function and metabolic health. Proteostasis is achieved via quality control pathways that support the generation and maintenance of correctly folded proteins. Organismal proteostasis is challenged by physiological and environmental risk factors and its impairment provokes the development of neurodegenerative and metabolic diseases. Among a variety of environmental cues, food quality and balanced nutrition play a major role in organismal health and can even decrease disease onset and burden of age-associated pathologies. Recent observations have demonstrated that dietary changes are linked to stress resistance and proteostasis. However, diet-induced proteostasis pathways of physiological and metabolic relevance currently remain largely unknown. To identify food-dependent response mechanisms that finetune and coordinate proteostasis pathways, we will take advantage of the multicellular model organism C. elegans, which mirrors many conserved human metabolic and proteostasis pathways and allows for well-defined feeding conditions. Despite the progress made in the characterization of stress response programs, the major challenge in the field is to advance our rudimentary understanding of the coordination of food perception and protein quality control. The overarching goal of the proposed research program is to unravel the molecular basis of diet-induced proteostasis pathways critical for physiological integrity and healthy aging. The underlying diet-inducible regulation mechanisms will be studied using the powerful genetic model of Caenorhabditis elegans, which mirrors many conserved human metabolic and proteostasis pathways and allows for well-defined feeding conditions.
Impact and perspectives:The innovative and interdisciplinary research program outlined here aims to establish novel mechanistic concepts for food-dependent regulation of proteostasis, which breaks ground for understanding how dietary composition and nutrients impact physiological integrity and healthy aging. Using the many experimental advantages provided by C. elegans and given the high degree of genetic and mechanistic conservation between worms and humans, the new molecular insights gained should provide a firm foundation for tackling the pathophysiology of age-associated diseases triggered by chronic malnutrition or high-calorie diets. Considering the importance of food quality and balanced nutrition for organismal physiology and healthy aging highlights the exciting potential of our proposed research program to ultimately develop new therapeutic options by targeting food-inducible proteostasis factors involved in age-associated diseases, including neurodegenerative disorders and obesity.
Impact and perspectives:
The innovative and interdisciplinary research program outlined here aims to establish novel mechanistic concepts for food-dependent regulation of proteostasis, which breaks ground for understanding how dietary composition and nutrients impact physiological integrity and healthy aging. Using the many experimental advantages provided by C. elegans and given the high degree of genetic and mechanistic conservation between worms and humans, the new molecular insights gained should provide a firm foundation for tackling the pathophysiology of age-associated diseases triggered by chronic malnutrition or high-calorie diets. Considering the importance of food quality and balanced nutrition for organismal physiology and healthy aging highlights the exciting potential of our proposed research program to ultimately develop new therapeutic options by targeting food-inducible proteostasis factors involved in age-associated diseases, including neurodegenerative disorders and obesity.
4. Applied methods and model organisms:
The long-term objective of this project is to define proteostasis networks essential for stress resistance and tissue functionality. This innovative and interdisciplinary research program will combine state-of-the-art transcriptome/proteome analyses with opto- and chemical-genetics approaches, manipulation and measuring of neuronal signaling/activity along with large-scale genetic screenings to identify and characterize regulatory circuits modulating proteostasis. The conserved regulation of proteostasis networks will be studied in C. elegans, mammalian cell culture, and samples of disease-patients. Besides novel insights into sensory adaptation mechanisms this research project will set the ground to tackle the pathophysiology of age-associated diseases. Mechanistic insights into the crosstalk between metabolic changes, stress signals, and ubiquitin-dependent regulation will help to develop new therapeutic strategies for metabolic and neurodegenerative diseases. The model organism C. elegans allows an ideal combination of genetic, biochemical and in vivo imaging techniques to examine the dynamic cross talk between sensory perception and proteostasis networks.
Over the last years we established innovative degradation assays that allow to follow protein turnover in vivo. These assays were successfully used in genetic screens; subsequent whole genome sequencing/mapping techniques helped to find for example a new crosstalk between mitochondrial metabolism and cytosolic protein degradation pathways. In most projects we were able to transfer the findings made in nematodes into human cell culture models, which are often related to age-associated diseases.
5. Desirable skills and qualifications:
We are seeking a highly motivated PhD student to join our enthusiastic and collaborative group. Successfulapplicants should have a solid background in molecular biology and experience in cell biology, genetics, or biochemistry. Candidates should have demonstrated outstanding performance through their undergraduate studies. Besides creativity, a strong ability for problem solving through analytical thinking combined with an enthusiasm for scientific research is highly desirable. Additionally, we expect good communication skills, fluent English and the ability for teamwork.
- Finger F., Ottens F.,Springhorn A., Drexel T., Proksch L., Metz S., Cochella L.,and Hoppe T. (2019). Olfaction regulates organismal proteostasis and longevity via miRNA-dependent signaling. Nature Metabolism 1, 350–59.
- Tawo R., Pokrzywa W., Kevei E., Akyuz M.E., Balaji V., Arian S., Höhfeld J., and Hoppe T. (2017). The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover. Cell 169, 470-82.
- Ackermann L., Schell M., Pokrzywa W., Kevei E., Gartner A., Schumacher B., and Hoppe T. (2016).E4 ligase specific ubiquitylation hubs coordinate DNA double strand break repair and apoptosis. Nat Struct Mol Biol. 23, 995-1002.
- Segref, A., Kevei, É., Pokrzywa, W., Schmeisser, K., Mansfeld, J., Livnat-Levanon, N., Ensenauer, R., Glickman, M.H., Ristow, M., and Hoppe, T. (2014). Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system. Cell Metab. 19, 642-652.
- Gazda, L., Pokrzywa, W., Hellerschmied, D., Löwe, T., Forné, I., Mueller-Planitz, F., and Hoppe, T.*, and Clausen, T. (2013). The myosin chaperone UNC-45 is organized in tandem modules to support myofilament formation in C. elegans. Cell 152, 183-195. *co-corresponding
- Kuhlbrodt, K., Janiesch, P.C., Kevei, É., Segref, A., Barikbin, R., and Hoppe, T. (2011). The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis. Nat. Cell Biol.13, 273-281.
- Franz, A., Orth, M., Pirson, P.A., Sonneville, R., Blow, J.J., Gartner, A., Stemmann, O., Hoppe, T. (2011). CDC-48/p97 coordinates CDT-1 degradation with GINS chromatin dissociation to ensure faithful DNA replication. Mol Cell. 44, 85-96.
- Janiesch, P.C., Kim, J., Mouysset, J., Barikbin, R., Lochmüller, H., Cassata, G., Krause, S., and Hoppe, T. (2007). The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy. Nat. Cell Biol. 9, 379-390.
- Hoppe, T., Cassata, G., Barral, J.M., Springer, W., Hutagalung, A.H., Epstein, H.F., and Baumeister R. (2004). Regulation of the myosin-directed chaperone UNC-45 by a novel E3/E4-multiubiquitylation complex in C. elegans. Cell 118, 337-349.
- Hoppe, T., Matuschewski, K., Rape, M., Schlenker, S., Ulrich, H.D., and Jentsch, S. (2000). Activation of a Membrane-Bound Transcription Factor by Regulated Ubiquitin/Proteasome-Dependent Processing. Cell102, 577-586.