Protein Phosphatase 1 dephosphorylates TDP-43 and suppresses its function in tau exon 10 inclusion

Transactive response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing, including alternative splicing of tau exon 10. Pathological TDP-43 is hyperphosphorylated. However, how do the protein phosphatase(s) (PP) regulate TDP-43 phosphorylation is unclear. Here, we found that both PP1 and PP2A were coimmunoprecipitated with TDP-43. Treatment with calyculin A, but not with okadaic acid, increased TDP-43 phosphorylation at Ser379, Ser403/404, and Ser409/410 in cultured cells. PP1α, PP1β, and PP1γ interacted with TDP-43. Overexpression of PP1α and PP1γ, but not PP1β, suppressed TDP-43 phosphorylation at Ser403/404 and Ser409/410 and TDP-43-induced tau exon 10 inclusion. These findings suggest that PP1α and PP1γ regulate TDP-43 phosphorylation and its function in tau exon 10 inclusion mainly through its phosphorylation at Ser403/404 and Ser409/410.