Cell-to-cell propagation of infectious cytosolic protein aggregates
Cell-to-cell propagation of infectious cytosolic protein aggregates
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DOI：
10.1073/pnas.1217321110
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发表时间：
2013-04-09
影响因子：
11.1
通讯作者：
Vorberg, Ina M.
中科院分区：
文献类型：
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作者：
Hofmann, Julia P.;Denner, Philip;Vorberg, Ina M.
朊病毒是一种自我模板的蛋白质构象，通过招募和将同型蛋白质转化为生长的蛋白质聚集体来复制。最初被确定为传染性海绵状脑病的病原体，现在越来越多的证据表明，朊病毒样现象在自然界中比以前预期的更常见。与在细胞质中复制的真菌朊病毒不同，源自前体蛋白PrP的哺乳动物朊病毒的繁殖仅限于细胞膜或内吞囊泡。在这里，我们证明了细胞质蛋白聚集体也可以作为哺乳动物细胞的感染性实体。当在哺乳动物细胞质中表达时，源自酵母翻译终止因子Sup35的朊病毒结构域NM的蛋白聚集体持续繁殖并侵入邻近细胞，从而诱导NM的自我延续聚集状态。细胞接触是有效感染的必要条件。聚集物也可以在原代星形胶质细胞、神经元和器官型培养物中被诱导，这表明这种现象并不局限于永生化细胞。我们的数据对于理解与人类疾病相关的蛋白质聚集的朊病毒样现象以及在哺乳动物中发现的越来越多的淀粉样蛋白具有重要意义。
Prions are self-templating protein conformers that replicate by recruitment and conversion of homotypic proteins into growing protein aggregates. Originally identified as causative agents of transmissible spongiform encephalopathies, increasing evidence now suggests that prion-like phenomena are more common in nature than previously anticipated. In contrast to fungal prions that replicate in the cytoplasm, propagation of mammalian prions derived from the precursor protein PrP is confined to the cell membrane or endocytic vesicles. Here we demonstrate that cytosolic protein aggregates can also behave as infectious entities in mammalian cells. When expressed in the mammalian cytosol, protein aggregates derived from the prion domain NM of yeast translation termination factor Sup35 persistently propagate and invade neighboring cells, thereby inducing a self-perpetuating aggregation state of NM. Cell contact is required for efficient infection. Aggregates can also be induced in primary astrocytes, neurons, and organotypic cultures, demonstrating that this phenomenon is not specific to immortalized cells. Our data have important implications for understanding prion-like phenomena of protein aggregates associated with human diseases and for the growing number of amyloidogenic proteins discovered in mammals.