Amino acid sensing and lysosomal signaling complexes

Amino acid pools in the cell are monitored by dedicated sen-sors, whose structures are now coming into view. The lyso-somal Rag GTPases are central to this pathway, and the regulation of their GAP complexes, FLCN-FNIP and GATOR1, have been worked out in detail. For FLCN-FNIP, the entire chain of events from the arginine transporter SLC38A9 to substrate-specific mTORC1 activation has been visualized. The structure GATOR2 has been determined, hinting at an ordering of amino acid signaling across a larger size scale than anticipated. The centerpiece of lysosomal signaling, mTORC1, has been revealed to recognize its substrates by more nuanced and substrate-specific mechanisms than previous appreciated. Beyond the well-studied Rag GTPase and mTORC1 machinery, another lysosomal amino acid sensor/ effector system, that of PQLC2 and the C9orf72-containing CSW complex, is coming into structural view. These de-velopments hold promise for further insights into lysosomal physiology and lysosome-centric therapeutics.