Cellular interaction with the environment
Cells integrate signals from their external and intracellular environment into fundamental processes such as growth, proliferation and survival. Nutrient availability and cellular metabolism play a crucial part in these cellular decisions. The mechanistic target of rapamycin complex 1 (mTORC1) pathway integrates growth factors, energy levels, glucose and amino acids to modulate protein, nucleotide and lipid synthesis. mTORC1 deregulation is critically involved in a variety of diseases including cancer and metabolic disorders. In spite of evidence on the implication of the lysosomal Ragulator/RAG GTPase complex in mTORC1 regulation, there is lack of mechanistic insight on amino acid sensing. Scientists on the EU-funded INNATEDNASENSOR (A proteomic screen to identify cytoplasmic DNA sensor proteins mediating type I interferon production) project set out to address this issue and unveil the mechanism by which cells sense amino acid availability. They discovered a previously uncharacterised amino acid transporter of the solute carrier family 38 (SLC38A9). This transporter is a key component of the machinery that activates mTOR signalling in response to amino acid levels. Experiments indicated that SLC38A9 could physically bind and transport amino acids, supporting a role at the core of the amino acid sensing mechanism. Apart from transport, amino acid engagement by SLC38A9 served as a mediator of allosteric signal transduction via its interaction with the Ragulator/RAG GTPase complex that ultimately activated mTOR. This finding could be used to interfere with the mTOR pathway as a treatment for pathological conditions such as cancer and metabolic disorders. In another part of the project, researchers investigated different immune receptors capable of sensing stress conditions and inducing a programmed necrosis pathway known as necroptosis. Although beneficial for the resolution of infection, necroptosis has been associated with inflammatory diseases. During INNATEDNASENSOR, scientists discovered that two FDA-approved anticancer agents, ponatinib and pazopanib, inhibited necroptosis by blocking key components of the necroptotic signalling pathway. These results highlight potential strategies for the treatment of pathologies caused or aggravated by necroptotic cell death.
Keywords
Metabolic status, cell death, amino acid, mTORC1, SLC38A9, Ragulator/RAG GTPase, necroptosis, ponatinib, pazopanib
