Aging Triggers Cytoplasmic Depletion and Nuclear Translocation of the E3 Ligase Mahogunin: A Function for Ubiquitin in Neuronal Survival

A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1. Once in the nucleus, MGRN1 potentiates the transcriptional cellular response to proteotoxic stress. Inhibition of MGRN1 impairs ATF3-mediated neuronal responsiveness to proteosomal stress and increases neuronal stress, while increasing MGRN1 ameliorates signs of neuronal aging, including cognitive performance in old animals. Our results imply that, among others, the strength of neuronal survival in a proteasomal deterioration background, like during aging, depends on the fine-tuning of ubiquitination-deubiquitination. [Display omitted] •Brain aging induces depletion and cytosol-to-nucleus relocation of the e3 ligase MGRN1•Nuclear entry is due to proteasome-impairment-dependent monoubiquitination of MGRN1•Nuclear MGRN1 potentiates the cellular transcriptional response to proteasome stress•Increased MGRN1 levels ameliorate signs of neuronal aging Benvegnù et al. demonstrate that, with aging, the neuroprotective e3 ligase MGRN1 relocates from the cytosol to the nucleus of neurons, where it associates with chromatin and potentiates the cellular response to proteotoxic stress. This nuclear shift is due to a proteasome-impairment-dependent increase of a monoubiquitinated form of MGRN1.