Abstract
PP2A is a major regulator of tau phosphorylation, which is principally regulated by an endogenous nuclear protein inhibitor 2 of PP2A (I2PP2A), also named SET. However, how SET is post-translationally regulated and translocates from the nucleus to the cytoplasm remain incompletely understood. Here we show SET is SUMOylated at K68 residue that induces its cytoplasmic retention, resulting in Alzheimer disease (AD) like tau pathology and cognitive defects. SET is predominantly SUMOylated at K68 that leads to its translocation from the nucleus to the cytoplasm and subsequently induces inhibition of PP2A and hyperphosphorylation of tau in HEK-293 cells. Moreover, overexpression of wild type SET significantly inhibits PP2A activity, leading to tau hyperphosphorylation, less synapse loss and cognitive deficits. Conversely, blocking SET SUMOylation via mutating Lys 68 to Arg rescues tau pathology and cognitive impairments in C57/BL6 mice infected with adeno-associated virus encoding SET. Further, β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of SET. Our findings suggest that SET SUMOylation stimulates its cytoplasmic retention and inhibits PP2A activity, consequently leading to tau hyperphosphorylation and cognitive impairments, which provides a new insight into the AD-like tau pathology.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder [5], which is characterized by the presence of two major neuropathological alterations: extracellular senile plaques consisting of β-amyloid (Aβ) and intracellular neurofibrillary tangles (NFTs) made up of the abnormally hyperphosphorylated tau [12, 15]
Studies have shown that tau and amyloid precursor protein (APP) are modified by SUMO [8, 9, 32, 41], whilst we have demonstrated that both beta-secretase (BACE1) at lysine 501 and tau at lysine 340 are the targets for SUMO-1 [3]
SUMOylation of SET leads to phosphatase 2A (PP2A) inhibition and tau phosphorylation Because SET is a specific inhibitor of PP2A [4], we investigated the effects of SET SUMOylation on the activity of PP2A
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder [5], which is characterized by the presence of two major neuropathological alterations: extracellular senile plaques consisting of β-amyloid (Aβ) and intracellular neurofibrillary tangles (NFTs) made up of the abnormally hyperphosphorylated tau [12, 15]. SUMO conjugation and binding to target proteins regulates a wide variety of important cellular. The functional aspects of SUMOylation include changes in protein-protein interactions, intracellular trafficking, protein aggregation and degradation [10, 17, 18, 27, 35, 38]. An increasing number of studies suggest the association of SUMOylation with AD progression and an increase of SUMO-1 level in AD brain [19]. Studies have shown that tau and amyloid precursor protein (APP) are modified by SUMO [8, 9, 32, 41], whilst we have demonstrated that both beta-secretase (BACE1) at lysine 501 and tau at lysine 340 are the targets for SUMO-1 [3]
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