Fnip1
Domain
The KY-finger orients the Cys degron for ubiquitination by the CRL2(FEM1B) complex.
Function
Binding partner of the GTPase-activating protein FLCN: involved in the cellular response to amino acid availability by regulating the non-canonical mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:23582324). Required to promote FLCN recruitment to lysosomes and interaction with Rag GTPases, leading to activation of the non-canonical mTORC1 signaling (By similarity). 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 inactivation of TFEB and TFE3 (By similarity). Together with FLCN, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (By similarity). 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 (By similarity). Acts as a scaffold to load client protein FLCN onto HSP90AA1/Hsp90 (By similarity). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (By similarity). 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 (PubMed:32941802). Required for B-cell development (PubMed:22709692, PubMed:27303042).
Post-translational modifications
Phosphorylated by AMPK in response to energetic stress (PubMed:37079666). Phosphorylation by AMPK in response to mitochondrial damage promotes inactivation of the non-canonical mTORC1 signaling, nuclear translocation of TFEB and TFE3, inducing transcription of lysosomal or autophagy genes (PubMed:37079666). Sequential phosphorylation by CK2 promotes its gradual interaction with HSP90AA1/Hsp90 (By similarity). Priming phosphorylation at Ser-937 is followed by relay phosphorylation at Ser-938, Ser-940, Ser-945 and Ser-947, promoting its gradual interaction with HSP90AA1/Hsp90 (By similarity). This leads to incremental inhibition of HSP90AA1/Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients (By similarity). Dephosphorylated by protein phosphatase 5 (PP5), promoting glycosylation by OGT (By similarity).
GlcNAcylation at Ser-937 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-1118 following glycosylation by OGT, leading to its degradation by the proteasome (By similarity). Ubiquitinated by the CRL2(FEM1B) complex in response to reductive stress: reductive stress causes reduction of the conserved Cys degron in FNIP1, followed by zinc-binding, zinc acting as a molecular glue for recognition by the CRL2(FEM1B) complex (PubMed:32941802, PubMed:34562363). Ubiquitination leads to FNIP1 degradation, and activation of mitochondria to recalibrate reactive oxygen species (ROS) (PubMed:32941802, PubMed:34562363).
Oxidation of the Cys degron in normal conditions promotes its stabilization by preventing recognition and ubiquitination by the CRL2(FEM1B) complex.
Sequence Similarities
Belongs to the FNIP family.
Cellular localization
- Lysosome membrane
- Cytoplasm
- Cytosol
- Localizes to lysosome membrane in amino acid-depleted conditions and relocalizes to the cytosol upon refeeding. Colocalizes with FLCN in the cytoplasm.
Alternative names
Kiaa1961, Fnip1, Folliculin-interacting protein 1