IISER MOHALI

Abstract: Cells adapt to the nutrient availability in the niche; especially environmental amino acid composition plays crucial roles in cellular growth and survival. Our previous work unveiled an mTORC1-independent function of the Rag GTPase–Ragulator machinery, in extracellular leucine starvation induced generation of lysosomal leucine storage, required for cellular protein synthesis under nutrient deprivation. Classically, Rag GTPases are well-known for their role in extracellular amino acid sensing and subsequently regulating mTORC1-pathway, in response to altered environmental nutritional status. Instead, we now found an unconventional mTOR-independent, novel regulatory role of Rag GTPases in cellular structural remodeling. Here, we have uncovered a novel fundamental pathway, involving non-canonical regulation of RagA/B GTPases in modulating epithelial–to-mesenchymal transition (EMT), in an autophagy-dependent, but mTOR-independent manner. We have also unraveled the major impact of this pathway in cell-cell connectivity and cell-cluster architectural patterning, essential for tissue shaping during neuronal development and tumorigenicity-metastasis in cancer biology. We predict that this Rag GTPase–autophagy-EMT axis may contribute to neuronal and cancer cell adaptation, by linking nutrient sensing to cellular remodelling, in response to nutrient fluctuations in the niche microenvironment.

Along the line, another piece of work in the lab revealed an extreme example of niche amino acid controlled cellular remodelling that could potentially be important for inter-cellular nutrient exchange. Here, we have discovered extracellular leucine deprivation counter-balanced by intracellular cystine as well as other essential amino acids, in turn triggering mTOR and Autophagy pathway dependent wide-scale cellular cytoskeletal re-structuring and formation of cell-to-cell Tunnelling Nanotube (TNT)-like connectors, acting as passage-way for trafficking of amino-acid loaded lysosomes and other organelles, between neighbouring cells. Simultaneously, in-vivo, in Caenorhabditis elegans model system, we found food deprivation, mimicking autophagy upregulation, leading to leucine rescuable wide-scale neuronal abnormalities.

These results altogether indicate an evolutionarily conserved amino acid homeostasis pathway regulating multiple cellular features, in vitro and in vivo, ultimately impacting cellular health and function across cell-types and species. These pathways altogether could play critical roles in degenerative disorders including neurodegeneration, lysosomal storage disorders (LSDs) and cancer that requires future research, which can potentially be beneficial for designing novel therapeutic strategies for these diseases.