mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate

Switching off lipid synthesis

30 January 2018

The discovery of a pathway that inhibits a complex involved in protein synthesis could lead to new treatments for diabetes, obesity and cancer.

Scientists at Curtin University in Australia, and colleagues, have uncovered a cellular pathway that inhibits the protein complex mTORC1. When this complex senses nutrients and energy in cells, it promotes the synthesis of proteins. mTORC1 has been implicated in many diseases and in the ageing process and its over-activation can lead to cellular damage. Restricting food intake has been found to inhibit mTORC1, increasing the lifespan of roundworms, fruit flies, mice and Rhesus monkeys.

The team found that depriving cells of a naturally-occurring substance involved in cell growth led to the synthesis of a lipid called PI(3,4)P₂ by means of an enzyme called PI3KC2β. This happens at the surface of vesicles responsible for cellular waste removal and ultimately inhibits mTORC1. Interestingly, when PI(3,4)P₂ is synthesized at the cell membrane, it can also facilitate mTORC1 activation. Pharmacologically targeting PI3KC2β-mediated synthesis of PI(3,4)P₂ could open new avenues for disease treatment.

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References

1. Science 356, 968–972 (2017). doi: 10.1126/science.aaf8310