Folliculin encoded by the <i>BHD</i> gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling

TLDR

Birt–Hogg–Dubé syndrome, caused by germ‑line mutations in the BHD(FLCN) gene, produces benign tumors and cysts, and folliculin’s tumor‑suppressor role is linked to the mTOR pathway, as seen in other hamartoma syndromes. The study identifies FNIP1 as a folliculin‑interacting protein and demonstrates its interaction with AMPK, a key regulator that negatively modulates mTOR activity. Phosphorylation of FNIP1 and FLCN by AMPK is reduced by AMPK inhibitors, while rapamycin and amino‑acid starvation diminish FLCN phosphorylation and FNIP1 overexpression enhances it, indicating that FLCN and FNIP1 participate in energy and nutrient sensing through AMPK and mTOR signaling.

Abstract

Birt–Hogg–Dubé syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by germ-line mutations in the BHD(FLCN) gene, which encodes a tumor-suppressor protein, folliculin (FLCN), with unknown function. The tumor-suppressor proteins encoded by genes responsible for several other hamartoma syndromes, LKB1, TSC1/2, and PTEN, have been shown to be involved in the mammalian target of rapamycin (mTOR) signaling pathway. Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5′ AMP-activated protein kinase (AMPK), a key molecule for energy sensing that negatively regulates mTOR activity. FNIP1 was phosphorylated by AMPK, and its phosphorylation was reduced by AMPK inhibitors, which resulted in reduced FNIP1 expression. AMPK inhibitors also reduced FLCN phosphorylation. Moreover, FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN may be regulated by mTOR and AMPK signaling. Our data suggest that FLCN, mutated in Birt–Hogg–Dubé syndrome, and its interacting partner FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.