E3 ligase adaptor FBXO7 contributes to ubiquitination and proteasomal degradation of SIRT7 and promotes cell death in response to hydrogen peroxide.

ABSTRACT

Parkinson's disease (PD) is a degenerative disorder of the central nervous system that affects 1% of the population over the age of 60. Although aging is one of the main risk factors for PD, the pathogenic mechanism of this disease remains unclear. Mutations in the F-box-only protein 7 (FBXO7) gene have been previously found to cause early onset autosomal recessive familial PD. FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates. Sirtuin 7 (SIRT7) is an NAD+-dependent histone deacetylase that regulates aging and stress responses. In this study, we identified FBXO7 as a novel E3 ligase for SIRT7 that negatively regulates intracellular SIRT7 levels through SCF-dependent Lys-48-linked polyubiquitination and proteasomal degradation. Consequently, we show that FBXO7 promoted the blockade of SIRT7 deacetylase activity, causing an increase in acetylated histone 3 levels at the Lys-18 and Lys-36 residues and the repression of downstream RPS20 gene transcription. Moreover, we demonstrate that treatment with hydrogen peroxide triggered the FBXO7-mediated degradation of SIRT7, leading to mammalian cell death. In particular, the PD-linked FBXO7-R498X mutant, which reduced SCF-dependent E3 ligase activity, did not affect the stability of SIRT7. Collectively, these findings suggest that FBXO7 negatively regulates SIRT7 stability and may suppress the cytoprotective effects of SIRT7 during hydrogen peroxide-induced mammalian cell death.