Human TorsinA can function in the yeast cytosol as a molecular chaperone.
Human TorsinA can function in the yeast cytosol as a molecular chaperone.
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DOI：
10.1042/bcj20170395
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发表时间：
2017-10-05
期刊：
影响因子：
--
通讯作者：
Tuite MF
中科院分区：
文献类型：
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作者：
Adam I;Jossé L;Tuite MF
TorsinA（TorA）是一种AAA+（与多种细胞活动相关的ATP酶）ATP酶，与1型肌张力障碍（DYT 1）相关，DYT 1是一种导致无法控制的肌肉运动的神经系统疾病。虽然DYT 1与TorA C-末端的3bp缺失相连，但TorA的生物学功能仍有待确定。 在这里，我们使用酵母酿酒酵母作为一个易于处理的体内模型，探讨TorA的功能。我们证明，TorA可以保护酵母细胞免受不同形式的环境压力，并表明在没有分子解聚酶Hsp 104的情况下，TorA可以在体内以ATP依赖的方式重新折叠热变性荧光素酶。然而，这种活性需要TorA从内质网转移到细胞质中，以便进入和处理细胞质蛋白质聚集体。此外，TorA的ATP酶活性的突变或化学失活阻断了该活性。我们还发现，TorA可以抑制[PSI+]的某些构象变体的繁殖，[PSI+]是内源性Sup 35蛋白的聚集朊病毒形式。最后，我们表明，虽然细胞定位在张力障碍相关的TorA突变体ΔE302-303中保持不变，但这种突变形式的TorA保护免受细胞应激和促进蛋白质重折叠的能力受损，与其功能丧失突变一致。
TorsinA (TorA) is an AAA+ (ATPases associated with diverse cellular activities) ATPase linked to dystonia type 1 (DYT1), a neurological disorder that leads to uncontrollable muscular movements. Although DYT1 is linked to a 3 bp deletion in the C-terminus of TorA, the biological function of TorA remains to be established. Here, we use the yeast Saccharomyces cerevisiae as a tractable in vivo model to explore TorA function. We demonstrate that TorA can protect yeast cells against different forms of environmental stress and show that in the absence of the molecular disaggregase Hsp104, TorA can refold heat-denatured luciferase in vivo in an ATP-dependent manner. However, this activity requires TorA to be translocated to the cytoplasm from the endoplasmic reticulum in order to access and process cytoplasmic protein aggregates. Furthermore, mutational or chemical inactivation of the ATPase activity of TorA blocks this activity. We also find that TorA can inhibit the propagation of certain conformational variants of [PSI+], the aggregated prion form of the endogenous Sup35 protein. Finally, we show that while cellular localisation remains unchanged in the dystonia-linked TorA mutant ΔE302-303, the ability of this mutant form of TorA to protect against cellular stress and to facilitate protein refolding is impaired, consistent with it being a loss-of-function mutation.