Watabe Masahiko, Nakaki Toshio
Department of Pharmacology; Teikyo University School of Medicine; Tokyo, Japan.
Commun Integr Biol. 2012 May 1;5(3):278-80. doi: 10.4161/cib.19473.
Misfolded proteins are prone to form aggregates, which interfere with normal cellular functions. In general, the ubiquitin-proteasome system degrades such misfolded proteins to avoid aggregation. If this system becomes impaired or overloaded, an inclusion-body-like organelle, aggresome will operate. Misfolded protein aggregates are transported to aggresome with a deacetylase HDAC6 and dynein motors along the microtubule network, and are then removed by autophagic degradation. Although it is well known that the aggresome has evolved to cope with an excess of protein aggregates, the mechanisms underlying its formation remain unclear. It is now established that the protein kinase CK2 is a crucial factor in aggresome assembly and clearance. In particular, this kinase phosphorylates HDAC6 on serine 458 in response to cellular stress which is caused by misfolded proteins. The resultant increase in HDAC6 deacetylase activity is crucial for both the recruitment of misfolded proteins to the aggresome and its clearance. Interestingly, serine 458 is conserved only in higher primates such as the humans and chimpanzee, but not in the mouse, rat, dog, bovine or rhesus macaque. This regulatory mechanism by phosphorylation of the serine residue may have evolutional significance.
错误折叠的蛋白质易于形成聚集体，从而干扰正常的细胞功能。一般来说，泛素-蛋白酶体系统降解此类错误折叠的蛋白质以避免聚集。如果该系统受损或过载，一种类似包涵体的细胞器——聚集体将会发挥作用。错误折叠的蛋白质聚集体通过脱乙酰酶HDAC6和动力蛋白沿着微管网络被转运至聚集体，然后通过自噬降解被清除。尽管众所周知聚集体的进化是为了应对过量的蛋白质聚集体，但其形成的潜在机制仍不清楚。现在已经确定蛋白激酶CK2是聚集体组装和清除的关键因素。特别是，这种激酶会响应由错误折叠的蛋白质引起的细胞应激，使HDAC6的丝氨酸458位点发生磷酸化。HDAC6脱乙酰酶活性的相应增加对于将错误折叠的蛋白质招募至聚集体及其清除都至关重要。有趣的是，丝氨酸458仅在人类和黑猩猩等高等灵长类动物中保守，而在小鼠、大鼠、狗、牛或恒河猴中则不保守。这种通过丝氨酸残基磷酸化的调节机制可能具有进化意义。
