RT Journal Article
SR Electronic
T1 ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101239
DO 10.26508/lsa.202101239
VO 5
IS 7
A1 Marta Wróbel
A1 Jarosław Cendrowski
A1 Ewelina Szymańska
A1 Malwina Grębowicz-Maciukiewicz
A1 Noga Budick-Harmelin
A1 Matylda Macias
A1 Aleksandra Szybińska
A1 Michał Mazur
A1 Krzysztof Kolmus
A1 Krzysztof Goryca
A1 Michalina Dąbrowska
A1 Agnieszka Paziewska
A1 Michał Mikula
A1 Marta Miączyńska
YR 2022
UL https://www.life-science-alliance.org/content/5/7/e202101239.abstract
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.