Cyclic AMP-Dependent Protein Kinase Phosphorylates TDP-43 and Modulates Its Function in Tau mRNA Processing
Cyclic AMP-Dependent Protein Kinase Phosphorylates TDP-43 and Modulates Its Function in Tau mRNA Processing
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环 AMP 依赖性蛋白激酶磷酸化 TDP-43 并调节其在 Tau mRNA 加工中的功能
DOI：
10.3233/jad-190368
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Liu, Fei
中科院分区：
文献类型：
--
作者：
Gu, Jianlan;Chu, Dandan;Liu, Fei
Trans-active response DNA-binding protein of 43 kDa (TDP-43) is a highly conserved and ubiquitously expressed nuclear protein. As a member of heterogeneous ribonucleoproteins, TDP-43 plays pivotal roles in mRNA processing. We recently found that TDP-43 promoted tau mRNA instability via acting on the 3' -untranslated region of its mRNA and enhanced tau exon 10 inclusion. TDP-43 is a phospho-protein. The function and the pathological aggregation of TDP-43 are regulated by the phosphorylation. In the present study, we determined phosphorylation of TDP-43 by cyclic AMP-dependent protein kinase (PKA). We found that TDP-43 was co-immunoprecipitated by and co-localized with PKA in the nucleus. PKA phosphorylated TDP-43 at Ser379, Ser403/404, and Ser409/410 in vitro and in cultured cells. Phosphorylation of TDP-43 at these sites enhanced mutually their phosphorylation by PKA in vitro and in cultured cells. Overexpression of PKA suppressed TDP-43's activity in promoting tau mRNA instability and tau exon 10 inclusion. These findings shed light on the role of PKA in phosphorylation and function of TDP-43. Downregulation of PKA signaling in AD brain may attenuate the impact of TDP-43 pathology in tau pathogenesis.
