Department of Pharmacology, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
J Cell Sci. 2011 May 1;124(Pt 9):1519-32. doi: 10.1242/jcs.081778. Epub 2011 Apr 12.
Misfolded protein aggregates elicit a stress response, and their clearance is crucial for cell survival. These aggregates are transported by cytoplasmic deacetylase HDAC6 and dynein motors to the aggresome via the microtubule network, and are removed by autophagic degradation. HDAC6 activity is necessary for both the transport and clearance of protein aggregates. However, the cellular factors that regulate HDAC6 activity remain unknown. Here we show that protein kinase CK2 is a crucial modulator of HDAC6 activity because CK2 directly phosphorylates HDAC6 and increases cytoplasmic deacetylase activity. Indeed, cells that expressed HDAC6 mutated at Ser458, a CK2-mediated phosphorylation site, failed to both form and clear aggresomes, and increased cytotoxicity. Interestingly, Ser458 is conserved only in higher primates, such as human and chimpanzee, but not in the rhesus macaque. These findings identify CK2 as a crucial protein involved in the formation and clearance of aggresomes, and hence in cell viability in response to misfolded protein stress.
错误折叠的蛋白质聚集体引发应激反应，其清除对于细胞存活至关重要。这些聚集体通过细胞质去乙酰化酶 HDAC6 和动力蛋白沿着微管网络运输到聚集体，然后通过自噬降解进行清除。HDAC6 的活性对于蛋白质聚集体的运输和清除都是必需的。然而，调节 HDAC6 活性的细胞因子仍然未知。本文中，作者表示蛋白激酶 CK2 是 HDAC6 活性的关键调节剂，因为 CK2 可以直接磷酸化 HDAC6 并增加细胞质去乙酰化酶活性。事实上，表达 CK2 介导的磷酸化位点 Ser458 发生突变的 HDAC6 的细胞既不能形成也不能清除聚集体，并且细胞毒性增加。有趣的是，Ser458 仅在高等灵长类动物（如人类和黑猩猩）中保守，而在恒河猴中则不存在。这些发现表明 CK2 是参与聚集体形成和清除的关键蛋白，因此在应对错误折叠蛋白应激时与细胞活力有关。
