Loss of the C.elegans FLCN homologue, flcn-1, led to a 21% increase in lifespan (Gharbi et al., 2013). The increased longevity observed in these FLCN-null animals was due to increased resistance to stress, and was dependent of Hif signalling, but not insulin signalling (Gharbi et al., 2013). Induction of autophagy also increases longevity in C. elegans (Schiavi et al., 2013).

Possik et al. (2014) used the same C. elegans model as Gharbi et al. to investigate the role of flcn-1 in metabolic stress, and also found that loss of flcn-1 led to increased stress resistance, although the authors did not observe increased lifespan. They found that flcn-1 deletion led to constitutive activation of the C. elegans homologue of AMPK, aak2, which led to higher autophagic flux, higher levels of intracellular ATP, thus increasing stress resistance by inhibiting apoptosis (Possik et al., 2014). These findings were replicated in mouse embryonic fibroblasts, suggesting that this pathway is evolutionarily conserved in mammals (Possik et al., 2014).

Increased autophagy was observed in DBHD-null Drosophila (Liu et al., 2013) and FLCN inhibits the activity of TFEB and TFE3 (Martina et al., 2014, Petit et al., 2013), which are transcription factors for autophagy genes, suggesting that FLCN may inhibit autophagy. Additionally, FNIP1 has been found to interact with the autophagy protein GABARAP (Behrends et al., 2010), further suggesting a role for FLCN in this process.

FLCN also inhibits autophagy induction by inhibiting the accumulation of LC3B, and promoting the accumulation of LC3C (Bastola et al., 2013). These experiments were conducted in 786-O cells, which are a model for VHL syndrome, and showed that FLCN is partially responsible for the tumour suppressor action of VHL in ccRCC. Additionally, two studies  have found that when treated with the chemotherapy Paclitaxel or radiotherapy, autophagy was induced via increased MEK–ERK signalling in FLCN-null but not FLCN-expressing cells, as shown by increased numbers of autophagosomes, increased levels of LC3B and decreased levels of p62 (Zhang et al., 2013, Zhang et al., 2014).

Taken together, these results suggest that FLCN usually inhibits autophagy. However, autophagic flux was found to be reduced in the heart tissues of mice with FLCN deleted in their cardiac cells, as shown by reduced AMPKα phosphorylation at T172, and reduced ULK1 phosphorylation at S555. Furthermore, FLCN enhances basal autophagic flux through its interaction with the autophagy proteins GABARAP and ULK1 (Dunlop et al., 2014). Dunlop et al. (2014) also show that reduced autophagy is likely to contribute to renal tumorigenesis in BHD, as autophagy is reduced in patient tumours – as measured by increased SQSTM1 and GABARAP expression – and BHD patient FLCN mutations that truncate the C-terminal end of the protein show reduced binding to GABARAP.

Thus, FLCN’s role in autophagy is not straightforward.