A DNAJB Chaperone Subfamily with HDAC-Dependent Activities Suppresses Toxic Protein Aggregation
A DNAJB Chaperone Subfamily with HDAC-Dependent Activities Suppresses Toxic Protein Aggregation
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DOI：
10.1016/j.molcel.2010.01.001
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发表时间：
2010-02-12
期刊：
影响因子：
16
通讯作者：
Kampinga, Harm H.
中科院分区：
文献类型：
--
作者：
Hageman, Jurre;Rujano, Maria A.;Kampinga, Harm H.
错误折叠和聚集与几种蛋白质折叠疾病中的细胞毒性有关。分子伴侣的大型网络确保蛋白质质量控制。在这里，我们表明，在热休克蛋白70，热休克蛋白110，和热休克蛋白40（DNAJ）伴侣家族，DNAJB家族的一个亚类的成员（特别是DNAJB 6 b和DNAJB 8）是上级抑制剂的聚集和毒性的疾病相关的多聚谷氨酰胺蛋白。抗聚集活性在很大程度上独立于N-末端Hsp 70相互作用的J-结构域。相反，C-末端富含丝氨酸（SSF-SST）区域和C-末端尾部是必需的。SSF-SST区域参与底物结合、多分散寡聚复合物的形成以及与组蛋白脱乙酰酶（HDAC 4、HDAC 6、SIRT 2）的相互作用。抑制HDAC 4降低DNAJ 138功能。DNAJB 8在两个保守的C-末端赖氨酸（不参与底物结合，但在抑制蛋白质聚集中发挥作用）处被乙酰化。结合起来，我们的数据提供了HDAC和DNAJ在抑制细胞毒性蛋白聚集方面的功能联系。
Misfolding and aggregation are associated with cytotoxicity in several protein folding diseases. A large network of molecular chaperones ensures protein quality control. Here, we show that within the Hsp70, Hsp110, and Hsp40 (DNAJ) chaperone families, members of a subclass of the DNAJB family (particularly DNAJB6b and DNAJB8) are superior suppressors of aggregation and toxicity of disease-associated polyglutamine proteins. The antiaggregation activity is largely independent of the N-terminal Hsp70-interacting J-domain. Rather, a C-terminal serine-rich (SSF-SST) region and the C-terminal tail are essential. The SSF-SST region is involved in substrate binding, formation of polydisperse oligomeric complexes, and interaction with histone deacetylases (HDAC4, HDAC6, SIRT2). Inhibiting HDAC4 reduced DNAJ 138 function. DNAJB8 is (de)acetylated at two conserved C-terminal lysines that are not involved in substrate binding, but do play a role in suppressing protein aggregation. Combined, our data provide a functional link between HDACs and DNAJs in suppressing cytotoxic protein aggregation.