DnaJC7 specifically regulates tau seeding.
DnaJC7 specifically regulates tau seeding.
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DOI：
10.7554/elife.86936
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发表时间：
2023-06-30
期刊：
影响因子：
7.7
通讯作者：
Diamond MI
中科院分区：
文献类型：
--
作者：
Perez VA;Sanders DW;Mendoza-Oliva A;Stopschinski BE;Mullapudi V;White CL;Joachimiak LA;Diamond MI
神经退行性tau病是由有毒tau蛋白聚集引起的。这似乎涉及基于模板的播种事件，由此tau单体改变构象并被招募到一个不断增长的聚集体。几个伴侣蛋白大家族，包括hsp70和J结构域蛋白（jdp），共同调节细胞内蛋白如tau的折叠，但协调这种活性的因素尚不清楚。JDP DnaJC7结合tau蛋白并减少其细胞内聚集。然而，尚不清楚这是DnaJC7特有的，还是其他jdp也可能涉及到类似的问题。我们在细胞模型中使用蛋白质组学来确定DnaJC7与不溶性tau共纯化并与细胞内聚集体共定位。我们分别敲除了每一种可能的JDP，并测试了对细胞内聚集和播种的影响。敲除DnaJC7降低了总清除率，增加了细胞内的tau种子。这取决于DnaJC7的J结构域（JD）刺激Hsp70 atp酶活性的能力，因为JD突变阻断了这种相互作用，从而取消了保护活性。DnaJC7的JD和底物结合位点的疾病相关突变也破坏了其保护活性。因此，DnaJC7特异性地与Hsp70合作调控tau聚集。
Neurodegenerative tauopathies are caused by accumulation of toxic tau protein assemblies. This appears to involve template-based seeding events, whereby tau monomer changes conformation and is recruited to a growing aggregate. Several large families of chaperone proteins, including Hsp70s and J domain proteins (JDPs), cooperate to regulate the folding of intracellular proteins such as tau, but the factors that coordinate this activity are not well known. The JDP DnaJC7 binds tau and reduces its intracellular aggregation. However, it is unknown whether this is specific to DnaJC7 or if other JDPs might be similarly involved. We used proteomics within a cell model to determine that DnaJC7 co-purified with insoluble tau and colocalized with intracellular aggregates. We individually knocked out every possible JDP and tested the effect on intracellular aggregation and seeding. DnaJC7 knockout decreased aggregate clearance and increased intracellular tau seeding. This depended on the ability of the J domain (JD) of DnaJC7 to stimulate Hsp70 ATPase activity, as JD mutations that block this interaction abrogated the protective activity. Disease-associated mutations in the JD and substrate binding site of DnaJC7 also abolished its protective activity. DnaJC7 thus specifically regulates tau aggregation in cooperation with Hsp70.