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FBXO10 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ligase whose effective substrate spectrum depends on regulated localization across the plasma membrane, cytoplasm/mitochondria, endomembrane/lysosomal pathway, and outer mitochondrial membrane.
"Across the evidence base, FBXO10 is increasingly understood not as a single-compartment factor but as a substrate receptor whose effective substrate spectrum depends on regulated localization—e.g., plasma membrane (palmitoylation; HGAL pathway per review), cytoplasmic/mitochondria-associated pools (BCL2), endomembrane/lysosomal trafficking (RAGE), and OMM targeting controlled by geranylgeranylation (PGAM5)."
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FBXO10 is geranylgeranylated at a C-terminal CaaX motif (C953), which is required for stable targeting to the outer mitochondrial membrane, where it forms a mitochondrial SCF(FBXO10) with SKP1 and CUL1.
"A major 2024 advance is that FBXO10 can be **post-translationally geranylgeranylated** at a C-terminal CaaX motif (C953), which is required for its stable targeting to the **outer mitochondrial membrane (OMM)**. This lipidation enables mitochondrial delivery via a PDE6δ/HSP90-dependent pathway linked to TOM70 docking, forming a mitochondrial SCF(FBXO10) complex with SKP1 and CUL1 at the OMM."
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At the outer mitochondrial membrane, FBXO10 promotes polyubiquitylation and degradation of the mitochondrial phosphatase PGAM5; loss of FBXO10 or a prenylation-deficient C953S mutant prevents PGAM5 degradation and disrupts mitochondrial morphology, bioenergetics, and myogenic differentiation.
"Proteomics and biochemical assays support **PGAM5** (a mitochondrial phosphatase) as an FBXO10-regulated OMM substrate: FBXO10 promotes PGAM5 polyubiquitylation and degradation in a manner sensitive to proteasome inhibition and cullin neddylation blockade. Loss of FBXO10 or expression of prenylation-deficient FBXO10(C953S) prevents PGAM5 degradation, disrupts mitochondrial morphology and bioenergetics, and impairs myogenic differentiation in human and murine myogenic models."
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FBXO10 was identified in an F-box screen as a factor that promotes ubiquitination and lysosomal degradation of the inflammatory receptor RAGE, recognized via cytoplasmic K374 and the phosphorylation-sensitive S391.
"FBXO10 was identified in an F-box screen as a factor that decreases RAGE protein levels and accelerates RAGE degradation. FBXO10 depletion stabilizes RAGE, supporting endogenous control. RAGE recognition involves specific cytoplasmic residues (e.g., K374 and S391), consistent with the general paradigm that degrons and post-translational modification states influence SCF substrate engagement. In this study, RAGE undergoes monoubiquitination and is routed to lysosomal degradation."
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Engineered Fbxo10 loss-of-function mice show no discernible increase in BCL2 protein or B-cell accumulation, indicating that FBXO10 either does not regulate BCL2 in mice or functions redundantly with other ligases.
"A mouse genetics study engineered Fbxo10 loss-of-function alleles and observed no discernible increase in BCL2 protein or B-cell accumulation in mice, concluding that FBXO10 either does not regulate BCL2 in mice or functions redundantly with other ligases (suggesting candidates such as FBXO11 or ARTS-XIAP)."