FNIP1

This gene encodes a protein that binds to the tumor suppressor protein folliculin and to AMP-activated protein kinase (AMPK). The encoded protein participates in the regulation of cellular metabolism and nutrient sensing by modulating the AMPK and target of rapamycin signaling pathways. This gene has a closely related paralog that encodes a protein with similar binding activities. Both related proteins also associate with the molecular chaperone heat shock protein-90 (Hsp90) and negatively regulate its ATPase activity and facilitate its association with folliculin.

Folliculin Interacting Protein 1

Binding partner of the GTPase-activating protein FLCN: involved in the cellular response to amino acid availability by regulating the mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, PubMed:24081491).

In low-amino acid conditions, component of the lysosomal folliculin complex (LFC) on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, thereby inactivating mTORC1 and promoting nuclear translocation of TFEB and TFE3 (By similarity).

Upon amino acid restimulation, disassembly of the LFC complex liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent cytoplasmic retention of TFEB and TFE3 (By similarity).

Required to promote FLCN recruitment to lysosomes and interaction with Rag GTPases (PubMed:24081491).

Together with FLCN, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (PubMed:25126726).

In addition to its role in mTORC1 signaling, also acts as a co-chaperone of HSP90AA1/Hsp90: following gradual phosphorylation by CK2, inhibits the ATPase activity of HSP90AA1/Hsp90, leading to activate both kinase and non-kinase client proteins of HSP90AA1/Hsp90 (PubMed:27353360, PubMed:30699359).

Acts as a scaffold to load client protein FLCN onto HSP90AA1/Hsp90 (PubMed:27353360).

Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:27353360).

Also acts as a core component of the reductive stress response by inhibiting activation of mitochondria in normal conditions: in response to reductive stress, the conserved Cys degron is reduced, leading to recognition and polyubiquitylation by the CRL2(FEM1B) complex, followed by proteasomal (By similarity).

Required for B-cell development (By similarity).

Cellular response to starvation Source: UniProtKB
Immature B cell differentiation Source: UniProtKB
Negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
Negative regulation of TOR signaling Source: UniProtKB
Negative regulation of transcription by RNA polymerase II Source: UniProtKB
Positive regulation of B cell apoptotic process Source: UniProtKB
Positive regulation of peptidyl-serine phosphorylation Source: UniProtKB
Positive regulation of protein-containing complex assembly Source: ParkinsonsUK-UCL
Positive regulation of protein phosphorylation Source: UniProtKB
Positive regulation of TOR signaling Source: UniProtKB
Regulation of pro-B cell differentiation Source: UniProtKB
Regulation of protein phosphorylation Source: UniProtKB
TOR signaling Source: UniProtKB

Lysosome membrane; Cytosol. Localizes to lysosome membrane in amino acid-depleted conditions and relocalizes to the cytosol upon refeeding (PubMed:29848618). Colocalizes with FLCN in the cytoplasm (PubMed:18663353).

Sequential phosphorylation by CK2 promotes its gradual interaction with HSP90AA1/Hsp90 (PubMed:30699359). Priming phosphorylation at Ser-938 is followed by relay phosphorylation at Ser-939, Ser-941, Ser-946 and Ser-948, promoting its gradual interaction with HSP90AA1/Hsp90 (PubMed:30699359). This leads to incremental inhibition of HSP90AA1/Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients (PubMed:30699359). Dephosphorylated by protein phosphatase 5 (PP5), promoting glycosylation by OGT (PubMed:30699359). Phosphorylated by AMPK (PubMed:17028174).
GlcNAcylation at Ser-938 by OGT following dephosphorylation by protein phosphatase 5 (PP5) promotes ubiquitination and degradation by the proteasome.
Ubiquitinated through 'Lys-11' linkage of ubiquitin moieties at Lys-1119 following glycosylation by OGT, leading to its degradation by the proteasome (PubMed:30699359). Ubiquitinated by the CRL2(FEM1B) complex in response to reductive stress: reductive stress causes reduction of the conserved Cys degron in FNIP1, leading to recognition by the CRL2(FEM1B), subsequent FNIP1 degradation, and activation of mitochondria to recalibrate reactive oxygen species (ROS) (By similarity).
Oxidation of the Cys degron in normal conditions promotes its stabilization by preventing recognition and ubiquitination by the CRL2(FEM1B) complex.