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

摘要

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.