WISP1 neuroprotection requires FoxO3a post-translational modulation with autoregulatory control of SIRT1.

As a member of the secreted extracellular matrix associated proteins of the CCN family, Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4) is garnering increased attention not only as a potent proliferative entity, but also as a robust cytoprotective agent during toxic insults. Here we demonstrate that WISP1 prevents forkhead transcription factor FoxO3a mediated caspase 1 and caspase 3 apoptotic cell death in primary neurons during oxidant stress. Phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt1) are necessary for WISP1 to foster posttranslational phosphorylation of FoxO3a and sequester FoxO3a in the cytoplasm of neurons with protein 14-3-3. Through an autoregulatory loop, WISP1 also minimizes deacytelation of FoxO3a, prevents caspase 1 and 3 activation, and promotes an effective neuroprotective level of SIRT1 activity through SIRT1 nuclear trafficking and prevention of SIRT1 caspase degradation. Elucidation of the critical pathways of WISP1 that determine neuronal cell survival during oxidative stress may offer novel therapeutic avenues for neurodegenerative disorders.