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.
The overexpression of endogenous protein inhibitors of PP2A, SET and CIP2A, is tightly linked to the progression of various human cancers, as well as Alzheimer's disease.
These findings suggest that SET phosphorylation is involved in the neuronal apoptotic pathway in AD and provide a new insight into the mechanism of this pathology.
Our findings suggest that oxidative stress and inflammatory responses could result in abnormal SET gene expression, contributing to the tauopathy in AD pathogenesis.
These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.
In conclusion, the current study has identified a novel mechanism that causes cytoplasmic detention of SET with a new NLS-dependent CKII-associated phosphorylation of Ser9, suggesting that inhibition of CKII arrests cytoplasmic accumulation of SET and thus preserves PP2A activity in AD brains.