Protein inhibitor of activated STAT1 Ser⁵⁰³ phosphorylation‐mediated Elk‐1 SUMOylation promotes neuronal survival in APP/PS1 mice

Abstract

Background and Purpose: Protein inhibitor of activated STAT1 (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 the functional significance of these additional phosphorylation events are not known. The transcription factor Elk-1 remains SUMOylated under basal conditions, but the role of Elk-1 SUMOylation in brain is unknown. Here, we examined the functional significance of PIAS1-mediated Elk-1 SUMOylation in Alzheimer's disease (AD) using the APP/PS1 mouse model of AD and amyloid β (Aβ) microinjections in vivo. Experimental Approach: Novel phosphorylation site(s) on PIAS1 were identified by LC-MS/MS, and MAPK/ERK-mediated phosphorylation of Elk-1 demonstrated using in vitro kinase assays. Elk-1 SUMOylation by PIAS1 in brain was determined using in vitro SUMOylation assays. Apoptosis in hippocampus was assessed by measuring GADD45α expression by western blotting, and apoptosis of hippocampal neurons in 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 this phosphorylation determines PIAS1 E3 ligase activity. In rat brain, Elk-1 was SUMOylated by PIAS1, which decreased Elk-1 phosphorylation and down-regulated GADD45α expression. Moreover, lentiviral-mediated transduction of Elk-1-SUMO1 reduced the number of hippocampal 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, which functions as an endogenous defence mechanism against Aβ toxicity in vivo. Targeting Elk-1 SUMOylation could be considered a novel therapeutic strategy against AD. 1 | INTRODUCTION One of the two pathological hallmarks of Alzheimer's disease (AD) in the brains of AD patients is the accumulation of senile plaques, composed largely of amyloid β (Aβ) peptides (Aβ 1-40 and Aβ 1-42). Aβ, generated by sequential proteolytic cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase (De Strooper & Annaert, 2000), initiates a detrimental cascade that increases lipid peroxidation, free radical production, caspase activation, and DNA damage,

Neuronal activity‐induced SUMOylation of Akt1 by PIAS3 is required for long‐term potentiation of synaptic transmission

“…The SUMO ligases are demonstrated to facilitate the conjugations of SUMOs and substrates. The SUMO ligase PIASs family, including PIAS1, PIAS2, PIAS3, and PIAS4, are required for the SUMOylation of various proteins 34‐39 . In this study, our results reveal that neuronal activity promotes the interaction of Akt1 with PIAS1 and PIAS3, but has no effect on the binding between Akt1 with PIAS2 and PIAS4.…”

Loss of Arid1a Promotes Neuronal Survival Following Optic Nerve Injury

“…To further explore mechanisms underlying RGC survival mediated by Arid1a deletion, we performed the proteinprotein interactions (PPIs) of differentially expressed genes. Strikingly, we observed some of the 30 genes with the highest degree shown in the circular layout were related to neuronal survival, such as Stat1, Tlr2 (Figure 3D; Stivers et al, 2017;Liu et al, 2019).…”

MicroRNA‐150 and its target ETS‐domain transcription factor 1 contribute to inflammation in diabetic photoreceptors

“…While phosphorylated ELK1 promotes the transcription of downstream genes, SUMOylated ELK1 represses the transactivation activity 54,55 . Stress elevates the phosphorylation of ELK1 but removing the SUMOylation 56,57 . It is possible that decreased SUMOylated ELK1 in the cytoplasm partially contributes to the upregulation of cytoplasmic pELK1 S383 (Figures 5 and 6), which may explain the exacerbated inflammation in miR‐150‐knockdown cells.…”