Dr Michał TurekPracownia Fizjologii Molekularnej Zwierząt
A new proteostasis mechanism for the removal of protein aggregates and damaged mitochondria has recently been described. Within this process, cellular waste material is ejected from the cell via large vesicles, termed exophers. Our laboratory is interested in deciphering the regulation of muscular exopher formation and uncovering its additional roles that go beyond maintaining protein/organelle homeostasis.
Najważniejsze osiągnięcia badawcze
- We identified muscular exophers in Caenorhabditis elegans as a model organism.
- We found that exopher production in Caenorhabditis elegans is a non-cell autonomous process that is regulated by egg formation in the uterus, which is used to nourish and improve the growth rate of the next generation.
To maintain proper cellular protein homeostasis, the tight regulation of protein synthesis, protein degradation, and the subtle balance between these two processes must be maintained. New proteins are made on ribosomes, and unnecessary or damaged proteins are recycled predominantly by the ubiquitin-proteasome system and autophagy-lysosome pathway. Recently, a complementary proteostasis mechanism has been described in Caenorhabditis elegans neurons and murine cardiomyocytes. Under proteotoxic stress, neurons in worms can remove protein aggregates, damaged mitochondria, and the lysosome into neighboring tissues via large membrane-surrounded vesicles called exophers. Exophers are much larger than previously described vesicles (approximately 4 µm diameter), and their formation enables neurons to maintain their proper functionality during neurotoxic stress and aging (Melentijevic et al. 2017). Moreover, the ejection of dysfunctional mitochondria from cardiomyocytes by exophers was recently reported (Nicolas-Avila et al. 2020). The evolutionary conservation of this cellular material extrusion phenomenon suggests that it constitutes a significant but currently poorly understood pathway that serves to maintain protein/organelle homeostasis. Indeed, using specially designed fluorescent reporters, we observed that C. elegans’ body wall muscles also produce high levels of exophers that are also larger (up to 20 µm) than neuronal variants.
Using worms that express fluorescent reporters in body wall muscle cells, we found that exopher formation (exopheresis) is a non-cell autonomous process that is regulated by egg formation in the uterus. Our data suggest that exophers serve as transporters for muscle-generated yolk proteins that are used to nourish and improve the growth rate of the next generation. We propose that one of the roles of muscular exopheresis is to stimulate reproductive capacity, thereby influencing the adaptation of worm populations to current environmental conditions (Turek et al. 2020). These data served as a basis for our SONATA grant application, and the continuation of this project will be the main focus of our research group for the next few years.
We hypothesize that exophers may be a fundamental mechanism of the regulation of cellular function. Many questions remain unanswered about this process. Therefore, the research focus of our group for the next few years will include the following:
- What is the mechanism of exopheresis regulation?
- How does environmental information influence exopher generation?
- What is the role of the nervous system in the regulation of muscular exopheresis?
- What is the mechanism of the epigenetic regulation of exopheresis, and how can exopheresis influence transgenerational inheritance?
- Melentijevic et al. Nature 2017. doi: 10.1038/nature21362
- Nicolas-Avila et al. Cell. 2020. doi: 10.1016/j.cell.2020.08.031
- Turek et al. BioRxiv. 2020. doi: https://doi.org/10.1101/2020.06.17.157230
Brightfield microscopy, epi-fluorescent microscopy, confocal microscopy, high-throughput microscopic screens, optogenetics, calcium imaging, CRISPR/Cas9, transcriptomics, proteomics, behavioral assays, lifespan measurements.
- Wojciech Pokrzywa, Laboratory of Protein Metabolism in Development and Aging, International Institute of Molecular and Cell Biology in Warsaw, Poland, www.iimcb.gov.pl.
- Ulrike Topf, Institute of Biochemistry and Biophysics Polish Academy of Sciences, Poland, www.topf-lab.org
- Matylda Macias, Core Facility, International Institute of Molecular and Cell Biology in Warsaw, Poland, www.iimcb.gov.pl.
- Małgorzata Śliwińska, Laboratory of Imaging Tissue Structure and Function, Nencki Institute of Experimental Biology Polish Academy of Sciences, Poland, www.nencki.gov.pl
- Remigiusz Serwa, Proteomics Core Facility, Centre of New Technologies University of Warsaw, Poland, cent.uw.edu.pl
Nagrody i wyróżnienia
- Michał Turek. Participant in the 68th Lindau Nobel Laureate Meeting dedicated to Physiology/Medicine. 2018. Foundation Lindau Nobel Laureate Meetings, Germany
- Michał Turek. START Fellowship. 2017. Foundation for Polish Science, Poland.
- Michał Turek. The Max Planck Society fellowship for a postdoctoral fellow. 2015 – 2016. Max Planck Society, Germany.