FLCN and FNIP1/2 Act as a RagC/D GAP

Loss-of-function mutations in folliculin (FLCN) are associated with Birt-Hogg-Dubé syndrome, a hereditary cancer predisposition syndrome marked by hamartomas of the hair follicle, kidney, and lung, suggesting that FLCN acts as a tumor suppressor. Although the FLCN protein has no known biochemical function, other genes mutated in hamartoma syndromes, such as TSC1/2, PTEN, and LKB1, are known regulators of mTORC1 signaling. Consistent with a potential role for FLCN in this pathway, Tsun and colleagues found that binding of FLCN to either folliculin-interacting protein (FNIP) 1 or 2 was required for recruitment of mTORC1 to the lysosomal surface and its subsequent activation in response to amino acids. The FLCN–FNIP complex interacted with Ras-related GTP binding (Rag) proteins, which form an obligate heterodimer consisting of RagA or B and RagC or D that recruits mTORC1 to the lysosomal surface. Unexpectedly, the Rag heterodimer only bound to mTORC1 when RagC/D was in the GDP-bound state, a surprising finding given that GTPases are usually functional when they are in the GTP-bound state. FLCN–FNIP1/2 preferentially interacted with GTP-bound RagC/D and was a potent stimulator of RagC/D GTPase activity, indicating that FLCN and FNIP1/2 form a GTPase activating protein (GAP) for RagC/D. Although these findings establish a biochemical function for FLCN and refine our understanding of mTORC1 regulation, a role for FLCN as a positive regulator of mTORC1 is unexpected given that FLCN is considered a tumor suppressor. Additional studies are needed to determine how mTORC1 signaling is bypassed or reactivated in FLCN-mutant tumors.

Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell 2013 Oct 3 [Epub ahead of print].