research HIGHLIGHTS
KIDNEY CANCER This hypothesis was supported by studies revealing direct interaction between TFEB and a Rag GTPase Differential mTORC1 pathways in BHD dimer, which seemed to be via the A study in Nature has shed light or RagB (RagA/B) in complex with first 30 amino acids of the TFEB on the mechanisms underlying the RagC or RagD (RagC/D)) are in their sequence. Furthermore, insertion of These data pathogenesis of Birt–Hogg–Dubé active configuration. Rag activation the S6K TOS into TFEB made TFEB suggest that (BHD) syndrome, an autosomal is mediated by the GTPase-activating phosphorylation behaviour sensitive dominant inherited disorder caused proteins GATOR1 and FLCN in to RHEB depletion and, therefore, constitutive by germline loss of function (LOF) response to local nutrient levels. similar to S6K, further supporting the activation of mutations in the folliculin (FLCN) TFEB, a controller of cell metab hypothesis that differential substrate TFEB caused gene that predispose to benign and olism, is negatively regulated by recruitment mechanisms are respons by LOF of FLCN malignant renal tumours. mTORC1; phosphorylation of TFEB ible for the selective phosphorylation Napolitano and colleagues inves- by mTORC1 promotes the cytoplas of mTORC1 substrates. is implicated tigated the role of mechanistic target mic localization of TFEB and inhibits As FLCN, a repressor of TFEB in the renal of rapamycin complex 1 (mTORC1) its nuclear translocation. The team activity, is implicated in BHD syn- phenotype activity and its differential interactions first investigated whether TFEB drome, the team then investigated with downstream substrates. behaves differently to other mTORC1 whether the kidney phenotype of seen in BHD Activation of mTORC1 — which substrates, S6K and 4E-BP1, at patients with BHD syndrome is syndrome controls the cellular response to phosphorylation by exposing these induced by TFEB activation. First, environmental cues via kinase substrates to serum and amino acid they generated mice with a kidney- activity on various substrates — deprivation. They observed that, specific double knockout of FLCN occurs at the lysosomal membrane, whereas S6K and 4E-BP1 phospho- and TFEB and compared their pheno where it is mediated by the small rylation could be inhibited by both type to mice with kidney-specific GTPase Ras homologue enriched in serum and amino acid deprivation, knockout of Flcn alone. Whereas the brain (RHEB). RHEB is induced by only amino acid deprivation affected Flcn-knockout mice had massively growth factors and inhibited by the the subcellular localization and activ enlarged kidneys and died by post- tuberous sclerosis complex (TSC). ity of TFEB. Accordingly, siRNA natal day 30, as well as exhibiting Recruitment of mTORC1 to the silencing of RHEB and its homologue increased nuclear localization of TFEB lysosomal membrane occurs when RHEBL1 did not affect the phospho- and enhanced mTORC1 signalling, Rag GTPase heterodimers (RagA rylation, cytosolic localization or the double knockout mice were activity of TFEB, but did reduce the phenotypically normal and displayed FLCN phosphorylation of S6K and 4E-BP1. no signalling abnormalities. These data By contrast, knockdown of RagC and suggest that constitutive activation mTORC1 TFEB RagD impaired TFEB activation of TFEB caused by LOF of FLCN is and localization, an effect that could implicated in the renal phenotype seen be reversed by re-expression of either in BHD syndrome. “We showed that RagC or RagD. These data suggest that TFEB is the main driver of the cystic Normal phosphorylation of TFEB by mTORC1 and cancer phenotype of BHD syn- BHD syndrome is unaffected by alterations in the drome, as demonstrated by the full res- FLCN TSC–RHEB axis (which is activated by cue of the kidney phenotype in FLCN/ growth factors) but is sensitive to the TFEB double KO mice,” corresponding ↑↑↑ mTORC1 TFEB ↑↑↑ activation of Rag GTPases. author Andrea Ballabio tells Nature The requirement of interaction Reviews Urology. “The effect of TFEB with Rag GTPases for TFEB phos- on renal cystogenesis and tumorigene- phorylation by mTORC1 is curious, sis is due, at least in part, to its ability to as no other mTORC1 substrates upregulate mTORC1. This mechanism interact with Rag GTPases. The TFEB is not limited to BHD syndrome but protein sequence does not contain operates in other diseases associated a TOR signalling (TOS) motif (as is with kidney cysts and cancer.” found in S6K), leading the team to Annette Fenner hypothesize that TFEB phosphoryl- Renal cysts and tumours Original article Napolitano, G. et al. ation by mTORC1 might be via an A substrate-specific mTORC1 pathway underlies BHD, Birt–Hogg–Dubé; FLCN, folliculin; mTORC1, alternative substrate-recruitment Birt–Hogg–Dubé syndrome. Nature https://doi. mechanistic target of rapamycin complex 1. Image org/10.1038/s41586-020-2444-0 (2020) adapted courtesy of A. Ballabio. mechanism involving Rag GTPases.
NaTuRe ReviewS | UROlOgy volume 17 | SEPTEMBER 2020 | 485