FNIP1
Description
The FNIP1 (folliculin interacting protein 1) is a protein-coding gene located on chromosome 5.
Folliculin-interacting protein 1 (FNIP1) functions as a co-chaperone which inhibits the ATPase activity of the chaperone Hsp90 (heat shock protein-90) and decelerates its chaperone cycle. FNIP1 acts as a scaffold to load FLCN onto Hsp90. FNIP1 is also involved in chaperoning of both kinase and non-kinase clients.
== Co-chaperone function == FNIP1 does not have any known functional domains; however, based on amino acid sequence alignments, conserved regions were identified and named as A–D. The C-terminal domain of FNIP1 (amino acids 929–1,166 or fragment D) preferentially interacts with the middle domain of Hsp90. This fragment and the full-length FNIP1 are potent inhibitors/decelerator of Hsp90 ATPase activity. Small-molecule inhibitors that target the nucleotide-binding pocket of the N-terminal domain of Hsp90 also inhibit its ATPase activity and lead to degradation of the client proteins. However, FNIP1-mediated inhibition of Hsp90 ATPase activity appears to decelerate the chaperone cycle, not inhibit it completely, as overexpression of FNIP1 stabilizes and activates client proteins. This can also be reversed by the co-chaperone Aha1, which is the activator of the Hsp90 ATPase function and competes with FNIP1 for binding to Hsp90.
== Post-translational regulation == Casein-kinase-2 mediated sequential phosphorylation of the co-chaperone FNIP1 leads to incremental inhibition of Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients. O-GlcNAcylation antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 ubiquitination and proteasomal degradation.
FNIP1 (Folliculin-interacting protein 1) is a protein that plays a crucial role in cellular responses to amino acid availability by regulating the non-canonical mTORC1 signaling pathway. It interacts with the GTPase-activating protein FLCN, a key component of the pathway, and together they control the activity of the transcription factors TFEB and TFE3, which regulate autophagy and lysosomal biogenesis. FNIP1 is essential for FLCN recruitment to lysosomes and its interaction with Rag GTPases, ultimately activating the non-canonical mTORC1 signaling pathway. In low-amino acid conditions, FNIP1 forms part of the lysosomal folliculin complex (LFC) on lysosomal membranes, inhibiting FLCN's GTPase-activating activity and consequently inactivating mTORC1. This leads to the nuclear translocation of TFEB and TFE3, promoting autophagy and lysosomal biogenesis. Conversely, upon amino acid restimulation, the LFC complex disassembles, liberating FLCN's GTPase-activating activity, activating mTORC1, and ultimately inactivating TFEB and TFE3. Beyond its role in mTORC1 signaling, FNIP1 also functions as a co-chaperone of HSP90AA1/Hsp90, a molecular chaperone essential for the folding and stability of many proteins. Through gradual phosphorylation by CK2, FNIP1 inhibits the ATPase activity of HSP90AA1/Hsp90, leading to the activation of both kinase and non-kinase client proteins. Notably, FNIP1 acts as a scaffold for loading the client protein FLCN onto HSP90AA1/Hsp90, competing with the activating co-chaperone AHSA1 for binding to HSP90AA1. This competition provides a regulatory mechanism for the chaperoning of client proteins. FNIP1 also plays a critical role in the reductive stress response, preventing the activation of mitochondria in normal conditions. In response to reductive stress, FNIP1 is degraded by the proteasome, allowing for the activation of mitochondria. This protein is essential for B-cell development and is known to form homodimers and homomultimers, as well as heterodimers and heteromultimers with FNIP2. It interacts with a range of proteins including FLCN, HSPCA, AMPK subunits, HSP70, STIP1, PTGES3, CDC37, BRAF, GCR, CDK4, and ATP2A2.
FNIP1 is also known as IMD93.
