Phosphorylation of the N-terminal portion of tyrosine hydroxylase triggers proteasomal digestion of the enzyme
Phosphorylation of the N-terminal portion of tyrosine hydroxylase triggers proteasomal digestion of the enzyme
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DOI：
10.1016/j.bbrc.2011.03.020
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发表时间：
2011-04-08
影响因子：
3.1
通讯作者：
Ota, Akira
中科院分区：
文献类型：
--
作者：
Nakashima, Akira;Mori, Keiji;Ota, Akira
酪氨酸羟化酶（TH）是儿茶酚胺生物合成中的限速酶，其N末端对该酶的细胞内稳定性起着至关重要的作用。在本研究中，我们研究了 TH N 末端区域影响这种稳定性的机制。在 Ser31 和 Ser40 处磷酸化的 TH 分子主要位于 PC12D 细胞的细胞质中。然而，那些在 Ser19 处磷酸化的分子主要存在于细胞核中，而它们在细胞质中似乎可以忽略不计。蛋白酶体的抑制增加了在其 Ser19 和 Ser40 处磷酸化的 TH 分子的数量，尽管它没有增加在其 Ser31 处磷酸化的 TH 分子的数量。自噬的抑制不影响 TH 分子或其三种磷酸化形式的量。缺乏含有三个磷酸化位点的 N 端区域的人 TH 1 型缺失突变体在 PC12D 细胞中具有该酶的高稳定性。这些结果表明 TH N 末端部分的磷酸化通过泛素-蛋白酶体途径调节该酶的降解。 (C) 2011 Elsevier Inc. 保留所有权利。
Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis, and its N-terminus plays a critical role in the intracellular stability of the enzyme. In the present study, we investigated the mechanism by which the N-terminal region of TH affects this stability. TH molecules phosphorylated at their Ser31 and Ser40 were localized predominantly in the cytoplasm of PC12D cells. However, those molecules phosphorylated at Ser19 were found mainly in the nucleus, whereas they seemed to be negligible in the cytoplasm. The inhibition of proteasomes increased the quantity of TH molecules phosphorylated at their Ser19 and Ser40, although it did not increase that of TH molecules or that of TH phosphorylated at its Ser31. The inhibition of autophagy did not affect the amount of the TH molecule or that of its three phosphorylated forms. Deletion mutants of human TH type-1 lacking the N-terminal region containing the three phosphorylation sites possessed high stability of the enzyme in PC12D cells. These results suggest that the phosphorylation of the N-terminal portion of TH regulates the degradation of this enzyme by the ubiquitin-proteasome pathway. (C) 2011 Elsevier Inc. All rights reserved.