mTORC1 ACTIVATION BY ENDOLYSOSOMAL-DERIVED NUTRIENTS

Abstract

Cancer cells with oncogenic Ras activate macropinocytosis to acquire nutrients, which are degraded in lysosomes, leading to the activation of mTORC1 and promoting cell growth. Glutamine (Gln) is crucial for mTORC1 activation, particularly in nitrogen metabolism and homeostasis. However, the exact mechanism by which glutamine supports Rag-independent mTORC1 activation via endolysosomal-derived nutrients is unclear. Using CRISPR-Cas9 technology, key enzymes in glutamine nitrogen metabolism were targeted. Glutaminase (GLS) knockouts significantly reduced mTORC1 activation, while glutamate dehydrogenase (GLUD) and glutamine synthetase (GLUL) knockouts had lesser effects. The findings highlight the need for further investigation into glutamine’s role in mTORC1 activation. BioID identified AP-4E1 and UNK as Raptor interactors, suggesting new potential mechanisms in the Rag-independent pathway. Understanding these interactions could reveal novel insights into how endolysosomal nutrients activate mTORC1, offering a deeper understanding of mTORC1 regulation in Ras-driven cancer cell growth.