| Birt-Hogg-Dube syndrome (BHD) is an inherited neoplasia syndrome that predisposes affected individuals to skin hamartomas, lung cysts, pneumothorax and renal carcinoma. Mutations within the BHD locus (also known as FLCN) have been found associated with the disease. Almost all mutations in BHD patients cause a truncated FLCN protein product suggesting a loss-of-function mechanism leading to tumor formation. FLCN is highly conserved across species from yeast to humans suggesting an important biological function. Earlier this year, the exact molecular function of FLCN was still unclear. However, with the aid of the first crystal structure of folliculin carboxy-terminal domain we provide the first insight into the function of folliculin as a novel GTPase. Interestingly this GTPase activity is lost in a naturally occurring disease-causing mutant (C1844G). We then characterize the role of FLCN-1 in the nematode Caenorhabditis elegans in an attempt to determine the signalling pathway(s) to which FLCN-1 belongs. We report a novel role of FLCN-1 in C. elegans aging as a component of the insulin/IGF-1 signalling pathway. FLCN-1 regulates lifespan via a mechanism that is AAK-2/AMPK, DAF-16/FOXO and autophagy dependent. We demonstrate that FLCN-1 negatively regulates AAK-2 phosphorylation independent of the constitutively active PAR-4 kinase. Moreover, flcn-1 null mutants have elevated levels of beta oxidation of fatty acids, mitochondrial respiration and ROS generation all of which are dependent on AAK-2. We hypothesis that ROS generation stimulates autophagy activation as a downstream mechanism required for lifespan extension of flcn-1 null mutants. Taken together, these studies are aimed to identify the functional role of FLCN and to clarify its metabolic role in relation to AMPK in order to better understand its tumor suppressor function. |
