PT  - JOURNAL ARTICLE
AU  - Marta Wróbel
AU  - Jarosław Cendrowski
AU  - Ewelina Szymańska
AU  - Malwina Grębowicz-Maciukiewicz
AU  - Noga Budick-Harmelin
AU  - Matylda Macias
AU  - Aleksandra Szybińska
AU  - Michał Mazur
AU  - Krzysztof Kolmus
AU  - Krzysztof Goryca
AU  - Michalina Dąbrowska
AU  - Agnieszka Paziewska
AU  - Michał Mikula
AU  - Marta Miączyńska
TI  - ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway
AID  - 10.26508/lsa.202101239
DP  - 2022 Jul 01
TA  - Life Science Alliance
PG  - e202101239
VI  - 5
IP  - 7
4099  - https://www.life-science-alliance.org/content/5/7/e202101239.short
4100  - https://www.life-science-alliance.org/content/5/7/e202101239.full
SO  - Life Sci. Alliance2022 Jul 01; 5
AB  - Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of proteins residing in endosomal membranes. Here, we show that mammalian ESCRT-I restricts the size of lysosomes and promotes degradation of proteins from lysosomal membranes, including MCOLN1, a Ca2+ channel protein. The altered lysosome morphology upon ESCRT-I depletion coincided with elevated expression of genes annotated to biogenesis of lysosomes due to prolonged activation of TFEB/TFE3 transcription factors. Lack of ESCRT-I also induced transcription of cholesterol biosynthesis genes, in response to inefficient delivery of cholesterol from endolysosomal compartments. Among factors that could possibly activate TFEB/TFE3 signaling upon ESCRT-I deficiency, we excluded lysosomal cholesterol accumulation and Ca2+-mediated dephosphorylation of TFEB/TFE3. However, we discovered that this activation occurs due to the inhibition of Rag GTPase–dependent mTORC1 pathway that specifically reduced phosphorylation of TFEB at S122. Constitutive activation of the Rag GTPase complex in cells lacking ESCRT-I restored S122 phosphorylation and prevented TFEB/TFE3 activation. Our results indicate that ESCRT-I deficiency evokes a homeostatic response to counteract lysosomal nutrient starvation, that is, improper supply of nutrients derived from lysosomal degradation.