IIMCB researchers from the Laboratory of Cell Biology discover that the ESCRT-I protein complex functions to provide lysosomes with cargo destined for degradation from multiple sources including turnover of lysosomal membranes. Therefore, deficiency of ESCRT-I causes improper supply of cells with nutrients derived from lysosomal degradation, that was termed "lysosomal nutrient starvation". This in turn evokes homeostatic signalling responses, including activation of TFEB/TFE3 transcription factors that occurs due to inhibition of the Rag-mTORC1 pathway.
Lysosomes are organelles that in eukaryotic cells, play an indispensable role to degrade cargo delivered from endocytosis and autophagy, supplying cells with nutrients. Recently, these organelles gained a lot of attention because targeting their function emerged as a promising strategy to treat cancer. In a recent study published in Life Science Alliance, Marta Wróbel, Jarosław Cendrowski, Marta Miączyńska and their co-workers from IIMCB report that the ESCRT-I protein complex, in addition to its established functions in endocytosis and autophagy, also maintains lysosomal homeostasis. The study was performed with help of researchers from the Maria Skłodowska-Curie National Research Institute of Oncology in Warsaw.
The Miączyńska’s lab has been long studying the functions of endocytosis in health and disease, including cellular activities of Endosomal Sorting Complex Required for Transport (ESCRT) complexes that are involved in endolysosomal trafficking, i.e. delivery of internalized membrane proteins and exogenous molecules to lysosomes. In their newest work, the IIMCB scientists focused on the consequences of deficiency of the core components of ESCRT-I complex, namely Tsg101 and Vps28 proteins, on the morphology and function of lysosomes as well as intracellular signalling regulated by these organelles. The researchers uncovered that lack of ESCRT-I led to enlargement of lysosomes, due to inhibition of protein degradation from the lysosomal surface, and impaired delivery of cholesterol from endolysosomal trafficking. By RNA-sequencing approach the authors discovered that cells lacking ESCRT-I activated transcriptomic responses to counteract improper delivery of nutrients from lysosomes. These responses involved elevated expression of genes responsible for cholesterol biosynthesis or lysosomal biogenesis. In part, these transcriptional changes occurred due to activation of TFEB/TFE3 transcription factors via inhibition of Rag-GTPase-dependent mTORC1 pathway, that is a hallmark of impaired delivery of nutrients from lysosomes.
The results of this research may point to new strategies for cancer treatment based on targeting lysosomal function.
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Wróbel M, Cendrowski J, Szymańska E, Grębowicz-Maciukiewicz M, Budick-Harmelin N, Macias M, Szybińska A, Mazur M, Kolmus K, Goryca K, Dąbrowska M, Paziewska A, Mikula M, Miączyńska M. ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway. Life Sci Alliance 5(7):e202101239
See also our video summary
Model of homeostatic response to lysosomal nutrient starvation.
Left panel, functional ESCRT-I enables cargo delivery by endocytosis, autophagy and lysosomal membrane protein turnover to lysosomes that allows proper cell supply with nutrients.
Right panel, lack of ESCRT-I inhibits lysosomal membrane protein turnover that results in enlargement of lysosomes. Impaired cargo delivery to lysosomes from multiple sources causes lysosomal nutrient starvation manifested by induction of starvation-like transcriptional response regulated via Rag-mTORC1-dependent TFEB/TFE3 activation.
This work was supported by the TEAM grant (POIR.04.04.00-00-20CE/16–00) to M Miączyńska and by the HOMING grant (POIR.04.04.00-00-1C54/16-00) to J Cendrowski, both from the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund.