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首页> 外文期刊>Biochemistry >GSK3beta-dependent phosphorylation of the alphaNAC coactivator regulates its nuclear translocation and proteasome-mediated degradation.
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GSK3beta-dependent phosphorylation of the alphaNAC coactivator regulates its nuclear translocation and proteasome-mediated degradation.

机译：GNA3依赖于GSK3beta的alphaNAC共激活剂的磷酸化调节其核易位和蛋白酶体介导的降解。

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摘要

c-Jun is an immediate-early gene whose degradation by the proteasome pathway is required for an efficient transactivation. In this report, we demonstrated that the c-Jun coactivator, nascent polypeptide associated complex and coactivator alpha (alphaNAC) was also a target for degradation by the 26S proteasome. The proteasome inhibitor lactacystin increased the metabolic stability of alphaNAC in vivo, and lactacystin, MG-132, or epoxomicin treatment of cells induced nuclear translocation of alphaNAC. We have shown that the ubiquitous kinase glycogen synthase kinase 3beta (GSK3beta) directly phosphorylated alphaNAC in vitro and in vivo. Inhibition of the endogenous GSKappa3beta activity resulted in the stabilization of this coactivator in vivo. We identified the phosphoacceptor site in the C-terminal end of the coactivator, on position threonine 159. We demonstrated that the inhibition of GSK3beta activity by treatment of cells with the inhibitor 5-iodo-indirubin-3'-monoxime, as well as with a dominant-negative GSK3beta mutant, induced the accumulation of alphaNAC in the nuclei of cells. Mutation of the GSK3beta phosphoacceptor site on alphaNAC induced a significant increase of its coactivation potency. We conclude that GSK3beta-dependent phosphorylation of alphaNAC was the signal that directed the protein to the proteasome. The accumulation of alphaNAC caused by the inhibition of the proteasome pathway or the activity of GSK3beta contributes to its nuclear translocation and impacts on its coactivating function.
机译：c-Jun是即早基因，其蛋白酶体途径降解是有效反式激活所必需的。在此报告中，我们证明了c-Jun共激活因子，新生多肽相关复合物和共激活因子α（alphaNAC）也是26S蛋白酶体降解的目标。蛋白酶体抑制剂乳酸菌素增加了体内αNAC的代谢稳定性，而乳酸菌素，MG-132或环氧霉素处理细胞可诱导αNAC的核易位。我们已经显示了普遍存在的激酶糖原合酶激酶3beta（GSK3beta）在体外和体内直接磷酸化alphaNAC。内源性GSKappa3beta活性的抑制导致该共活化剂在体内的稳定。我们在共激活剂C末端C末端的159处确定了磷酸受体位点。我们证明了通过用抑制剂5-碘-靛玉红3'-一肟以及其他抑制剂处理细胞来抑制GSK3beta活性。显性阴性的GSK3beta突变体诱导了alphaNAC在细胞核中的积累。 alphaNAC上GSK3beta磷酸受体位点的突变导致其共激活潜能的显着提高。我们得出结论，αNAC的GSK3beta依赖性磷酸化是将蛋白质导向蛋白酶体的信号。由蛋白酶体途径的抑制或GSK3beta的活性引起的alphaNAC的积累有助于其核易位并影响其共激活功能。

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