Laboratory of Protein Metabolism in Development and Aging: Pokrzywa Laboratory

Description of Current Research

The proteome is defined as the entire set of proteins expressed in a given cell-type or organism, which can vary with time and physiological status. The integrity of the cellular proteome is supported by quality control networks. The human proteostasis network involves >1000 accessory factors and regulatory components, which govern protein synthesis, folding, and degradation. Otherwise, defective folding could result in increased abundance of toxic protein aggregates, which endanger the integrity of the entire proteome. Molecular chaperones additionally participate in refolding of damaged proteins that accumulate upon proteotoxic stress conditions. In case protein refolding cannot be sufficiently executed, chaperones team up with the ubiquitin/proteasome-system (UPS) or autophagy pathway to trigger degradation of unwanted proteins (Fig. 1). Recent studies in different organisms supported the idea that the activity of the 26S proteasome progressively declines during aging, although molecular aspects of this regulation have not been addressed. The goal of our research is to understand both, spatiotemporal control of protein quality control activity as well as substrate processing. We believe that deciphering the molecular mechanisms underlying the regulation of protein quality control interventions and substrate specificity could be the basis to develop novel therapeutic strategies to treat age-related diseases, including metabolic and neurodegenerative disorders.

As models, we are using Caenorhabditis elegans and human cells, and we are employing multi-disciplinary approaches ranging from genetics and molecular biology to biochemistry.

We focus on the following projects:
1. Development of fluorescent sensors to monitor the activity of cell-specific proteostasis.
2. Identification of modifiers of neuronal and glial proteostasis.
3. Regulation of amino acid metabolic enzymes in development and aging.
4. Role of circRNAs in the regulation of protein quality control.



Fig. 1. Illustrative representation of subcellular localization of various PQC Ub ligases.
E3 enzymes operating in quality control pathways (e.g., CHIP, Doa10, HUWE1, Listerin, Rsp5, and San1) and associated chaperones (in green and gray) are widely distributed in most subcellular compartments, including nucleus, cytoplasm, ER, and plasma membrane.