Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation
Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation
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DOI：
10.1073/pnas.1607215114
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发表时间：
2017-01-17
影响因子：
11.1
通讯作者：
James, Leo C.
中科院分区：
文献类型：
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作者：
McEwan, William A.;Falcon, Benjamin;James, Leo C.
阿尔茨海默病（AD）和其他神经退行性疾病与微管相关蛋白tau的细胞质聚集相关。最近的证据支持tau错误折叠（播种）的跨细胞转移作为受影响大脑内传播的机制，这一过程让人想起病毒感染。然而，尽管微生物病原体可以被免疫受体识别为非自身的，但错误折叠的蛋白质组装体逃避检测，因为它们是宿主衍生的。在这里，我们表明，当错误折叠的tau组件进入细胞，它们可以被检测到，并通过tau相关抗体介导的危险反应和胞质Fc受体三联基序蛋白21（TRIM 21）中和。我们开发了荧光，形态学为基础的播种试验，允许病理性tau聚集体的形成，在24小时内原位测量的存在下，皮摩尔浓度的tau种子。我们发现，抗tau抗体伴随tau种子进入细胞，在进入细胞后不久，它们就会招募TRIM 21。结合后，TRIM 21通过蛋白酶体和AAA ATP酶p97/VCP的活性以与感染性病毒类似的方式中和tau种子。这些结果表明，细胞内的抗病毒免疫可以被重定向到宿主来源的神经退行性疾病的病原体。
Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.