The (m)TOR pathway regulates cellular metabolism through sensing extra- and intracellular signals. TOR kinase in yeast (mTOR in mammals) assembles in two complexes. While the function of (m)TOR Complex 1 is well established, less is known about (m)TOR Complex 2, mainly due to the lack of specific inhibitors.

The study presents a small amphipathic molecule, palmitoylcarnitine, and its derivatives that inhibit (m)TORC2 by intercalating into the plasma membrane (PM) and decreasing its lipid order. The use of cholesterol, an order-modifying lipid, confirmed that (m)TORC2 is sensitive to the PM lipid order.

Even under the continued presence of palmitoylcarnitine, (m)TORC2 recovers from inhibition. We showed that the recovery requires a regulation loop between TORC2 and two sterol transporters, Lam2 and Lam4, suggesting the role of sterols in TORC2 recovery.

We present details of the connection between PM and (m)TORC2 regulation. These findings may shine a new light on pathologies involving the pathway.