Parkinson’s disease (PD) is characterized by the progressive loss of midbrain dopamine neurons in the substantia nigra. Mutations in the F-box only protein 7 gene ( Fbxo7 ) have been reported to cause an autosomal recessive form of early-onset familial PD. FBXO7 is a part of the SKP1-Cullin1-F-box (SCF) E3 ubiquitin ligase complex, which mediates ubiquitination of numerous substrates. FBXO7 also regulates mitophagy, cell growth, and proteasome activity. A member of the FOXO family, the transcription factor FOXO4, is also known to modulate several cellular responses, including cell cycle progression and apoptosis; however, the relationship between FBXO7 and FOXO4 has not been investigated. In this study, we determined that FBXO7 binds to FOXO4 and negatively regulates intracellular FOXO4 levels. Interestingly, we also found that FBXO7-mediated degradation of FOXO4 did not occur through either of two major proteolysis systems, the ubiquitin-proteasome system or the lysosome-autophagy pathway, although it was blocked by a caspase 8-specific inhibitor and caspase 8 -knockdown. Moreover, intracellular FOXO4 levels were greatly reduced in dopaminergic MN9D cells following treatment with neurotoxic 6-hydroxydopamine (6-OHDA), which was produced upon FBXO7-mediated and caspase 8-mediated proteolysis. Taken together, these results suggest that FOXO4 is negatively regulated in FBXO7-linked PD through caspase 8 activation, suppressing the cytoprotective effect of FOXO4 during 6-OHDA-induced neuronal cell death.

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Regulator of calcineurin 1 (RCAN1; also referred as DSCR1 or MCIP1) is located in close proximity to a Down syndrome critical region of human chromosome 21. Although RCAN1 is an endogenous inhibitor of calcineurin signaling that controls lymphocyte activation, apoptosis, heart development, skeletal muscle differentiation, and cardiac function, it is not yet clear whether RCAN1 might be involved in other cellular activities. In this study, we explored the extra-functional roles of RCAN1 by searching for novel RCAN1-binding partners. Using a yeast two-hybrid assay, we found that RCAN1 (RCAN1-1S) interacts with histone deacetylase 3 (HDAC3) in mammalian cells. We also demonstrate that HDAC3 deacetylates RCAN1. In addition, HDAC3 increases RCAN1 protein stability by inhibiting its poly-ubiquitination. Furthermore, HDAC3 promotes RCAN1 nuclear translocation. These data suggest that HDAC3, a new binding regulator of RCAN1, affects the protein stability and intracellular localization of RCAN1.