FBXO32
F-box only protein 32 (Atrogin-1) (Muscle atrophy F-box protein) (MAFbx)
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Endophilin-A, a well-characterized endocytic adaptor essential for synaptic vesicle recycling, has recently been linked to neurodegeneration. We report here that endophilin-A deficiency results in impaired movement, age-dependent ataxia, and neurodegeneration in mice. Transcriptional analysis of endophilin-A mutant mice, complemented by proteomics, highlighted ataxia- and protein-homeostasis-related genes and revealed upregulation of the E3-ubiquitin ligase FBXO32/atrogin-1 and its transcription factor FOXO3A. FBXO32 overexpression triggers apoptosis in cultured cells and neurons but, remarkably, coexpression of endophilin-A rescues it. FBXO32 interacts with all three endophilin-A proteins. Similarly to endophilin-A, FBXO32 tubulates membranes and localizes on clathrin-coated structures. Additionally, FBXO32 and endophilin-A are necessary for autophagosome formation, and both colocalize transiently with autophagosomes. Our results point to a role for endophilin-A proteins in autophagy and protein degradation, processes that are impaired in their absence, potentially contributing to neurodegeneration and ataxia.
MeSH Terms
- Acyltransferases
- Aging
- Animals
- Apoptosis
- Ataxia
- Autophagosomes
- Autophagy
- Brain
- Forkhead Box Protein O3
- HeLa Cells
- Hippocampus
- Homeostasis
- Humans
- Male
- Mice
- Mice, Knockout
- Movement Disorders
- Muscle Proteins
- Mutation
- Nerve Degeneration
- Parkinson Disease
- Proteasome Endopeptidase Complex
- Protein Binding
- SKP Cullin F-Box Protein Ligases
- Transcription, Genetic
- Ubiquitin
- Up-Regulation
Keywords
- FBXO32
- Parkinson’s disease
- ataxia
- autophagy
- endocytosis
- endophilin
- neurodegeneration
- next-generation sequencing
- protein homeostasis
- ubiquitin-proteasome system
A study was conducted to determine the changes that occur to proteolysis and related genes due to age, protein, and energy intake in high-yield broiler breeder hens (Gallus gallus). Cobb 700 broiler breeders were randomly assigned to one of six diets in a 2×3 factorial fashion. Two levels of energy (390 and 450 kcal/day) and three levels of protein (22, 24, and 26 g CP/day) were utilized. Protein turnover was determined in the left pectoralis at 22, 26, 31 and 44 weeks. Relative mRNA expression of calpain 2 (CAPN2), proteasome C2 subunit (PSMA1), and F box protein 32 (FBXO32) were determined via RT-PCR at 20, 25, and 44 weeks. Contrasts indicate fractional synthesis rate (FSR) and FBXO32 increase to a maximum at 25-26 weeks and a decrease thereafter. A significant drop in PSMA1 and FBXO32 was observed between 25 and 44 weeks and matched the decrease observed in FBR. No differences were detected in the levels of fractional synthesis and degradation, or the expression of CAPN2, PSMA1, and FBXO32, due to protein or energy intake. In summary, protein turnover was upregulated during the transition into sexual maturity and decreased thereafter. The observed changes in degradation appeared to be mediated by the ubiquitin-proteasome pathway.
MeSH Terms
- Aging
- Animal Feed
- Animals
- Chickens
- Dietary Proteins
- Energy Intake
- Female
- Gene Expression Regulation
- Mammary Glands, Animal
- Muscles
- Oviposition
- Proteolysis
- RNA, Messenger