PIAS1 Ser-503 phosphorylation-mediated Elk-1 SUMOylation promotes neuronal survival in APP/PS1 mice.

BACKGROUND AND PURPOSE: PIAS1 is phosphorylated by IKKα at Ser-90 in a PIAS1 E3 ligase activity-dependent manner. Whether PIAS1 is also phosphorylated at other residues, and what potential functional significance such additional phosphorylation events might have, are not known. The transcription factor Elk-1 remains SUMOylated under basal conditions, but the role of Elk-1 SUMOylation in the brain is unknown. Here, we examined the functional significance of PIAS1-mediated Elk-1 SUMOylation in the context of Alzheimer's disease (AD) using the APP/PS1 mouse model of AD and amyloid beta (Aβ) microinjection in vivo.

EXPERIMENTAL APPROACH: Novel phosphorylation site(s) on PIAS1 were identified by LC-MS/MS, and MAPK/ERK-mediated phosphorylation of Elk-1 was demonstrated using in vitro kinase assays. Elk-1 SUMOylation by PIAS1 in the brain was determined using in vitro SUMOylation assays. Apoptosis in the hippocampus was assessed by measuring GADD45α expression by Western blotting, and apoptosis of neurons in the hippocampus of APP/PS1 mice was assessed by TUNEL assay.

KEY RESULTS: Using LC-MS/MS, we identified a novel MAPK/ERK-mediated phosphorylation site on PIAS1 at Ser-503 and showed that this phosphorylation determines PIAS1 E3 ligase activity. In the rat brain, Elk-1 is SUMOylated by PIAS1, which decreases Elk-1 phosphorylation and downregulates GADD45α expression. Moreover, lentiviral-mediated transduction of Elk-1-SUMO1 in the hippocampus reduces the number of apoptotic neurons in APP/PS1 mice.

CONCLUSIONS AND IMPLICATIONS: MAPK/ERK-mediated phosphorylation of PIAS1 at Ser-503 determines PIAS1 E3 ligase activity. Moreover, PIAS1 mediates SUMOylation of Elk-1, and this modification functions as an endogenous defense mechanism against Aβ toxicity in vivo. Targeting Elk-1 SUMOylation could be considered a novel therapeutic strategy against AD.