Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3

Abstract

Folliculin interacting protein 1 (Fnip1) is a cytoplasmic protein originally discovered through its interaction with the master metabolic sensor 59 AMP-activated protein kinase (AMPK) and Folliculin, a protein mutated in individuals with Birt-Hogg-Dubé Syndrome. In response to low energy, AMPK stimulates catabolic pathways such as autophagy to enhance energy production while inhibiting anabolic pathways regulated by the mechanistic target of rapamycin complex 1 (mTORC1). We previously found that constitutive disruption of Fnip1 in mice resulted in a lack of peripheral B cells because of a block in B cell development at the pre-B cell stage. Both AMPK and mTORC1 were activated in Fnip1-deficient B cell progenitors. In this study, we found inappropriate mTOR localization at the lysosome under nutrient-depleted conditions. Ex vivo lysine or arginine depletion resulted in increased apoptosis. Genetic inhibition of AMPK, inhibition of mTORC1, or restoration of cell viability with a Bcl-x L transgene failed to rescue B cell development in Fnip1-deficient mice. Fnip1-deficient B cell progenitors exhibited increased nuclear localization of transcription factor binding to IgHM enhancer 3 (TFE3) in developing B cells, which correlated with an increased expression of TFE3-target genes, increased lysosome numbers and function, and increased autophagic flux. These results indicate that Fnip1 modulates autophagy and energy response pathways in part through the regulation of AMPK, mTORC1, and TFE3 in B cell progenitors.

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

“…We hypothesized that human FNIP1 deficiency may hamper B-cell metabolism similar to Fnip1-deficient mice [2][3][4][5][6][7][8] . Indeed, circulating P1 B-cells exhibited increased numbers of mitochondria and mitochondrial activity relative to healthy control (HC) B-cells ( Figure 1F and supplemental Figure 9).…”

“…Mouse Fnip1 consists of 1,165 amino acids and shares 91% amino acid identity with human FNIP1 5 . Fnip1 plays a nonredundant role in early B-cell development and metabolism, skeletal muscle fiber type specification, and cardiac function [2][3][4][5][6][7][8] . Our report confirms that the clinical and immunological phenotypes are strikingly overlapping (i.e., HCM, pre-excitation syndrome, and early and severe B-cell defect with agammaglobulinemia).…”

“…Disruption of Folliculin Interacting Protein 1 (FNIP1) alters the essential metabolic regulators AMPK and mTOR ( Figure 1A), resulting in profound B-cell deficiency and decreased NKT cells, hypertrophic cardiomyopathy (HCM), and pre-excitation syndrome [2][3][4][5][6][7][8] . Contemporarily, another group 9 clinically described two families with inborn FNIP1 deficiency with hypogammaglobulinemia, intermittent neutropenia, and HCM.…”

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

“…Folliculin interacting protein 1 (FNIP1) is an adaptor protein originally identified through its interaction with folliculin (FLCN) and AMPK [18]. Previous studies have implicated that FNIP1 influences cellular metabolic regulators such as AMPK and mTOR signaling [19][20][21][22][23]. However, the exact roles of FNIP1 in modulating AMPK or mTOR signaling remain unclear.…”

“…Whole body deletion of Fnip1 in mice has recently been shown to increase type I muscle fiber composition and activate AMPK signaling [20], whereas it has also been shown that mice with loss of FNIP1 in muscle actually have reduced phosphorylation of the catalytic α subunit of AMPK (Thr172) [21]. Similarly, both suppression and activation of mTOR signaling by FNIP1 have also been reported [20,21,23,24]. Collectively, the results of previous studies suggest a role for FNIP1 in muscle fiber type specification and metabolism.…”