Inducible HSP70 is critical in preventing the aggregation and enhancing the processing of PMP22.
Inducible HSP70 is critical in preventing the aggregation and enhancing the processing of PMP22.
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DOI：
10.1177/1759091415569909
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发表时间：
2015-01
期刊：
影响因子：
4.7
通讯作者：
Notterpek L
中科院分区：
文献类型：
--
作者：
Chittoor-Vinod VG;Lee S;Judge SM;Notterpek L
伴侣蛋白，也称为热休克蛋白（HSP），与蛋白质短暂相互作用，以帮助其折叠，运输和降解，从而直接影响新合成分子的运输。分子伴侣的诱导为蛋白质错误折叠疾病提供了一种潜在的治疗方法，如外周髓鞘蛋白22（PMP 22）相关的周围神经病变。与脱髓鞘雪旺细胞表型相关的PMP 22的胞质聚集体导致蛋白酶体活性的抑制和蛋白酶抑制机制的激活，包括热休克途径。虽然已经反复观察到伴侣蛋白在防止聚集和改善PMP 22的运输方面的有益作用，但事件中对HSP 70的需求仍然难以捉摸。在这项研究中，我们表明，在PMP 22复制相关的Charcot-Marie-Tooth病1A型患者的成纤维细胞中，FDA批准的小分子分子伴侣途径的激活增加了HSP 70的表达，并减弱了蛋白酶体功能障碍。使用来自HSP70.1/3−/−（诱导型HSP 70）小鼠模型的细胞，我们证明了在蛋白毒性应激下，这种分子伴侣在防止PMP 22聚集方面至关重要，并且这种作用是由宏自噬辅助的。当在稳态下检查时，HSP 70似乎在野生型PMP 22的运输中起次要作用，而它对于防止聚集倾向的Trembler-J-PMP 22的积累至关重要。HSP 70有助于Trembler-J-PMP 22通过高尔基体的加工，并通过Rab 7阳性囊泡将其递送至溶酶体。总之，这些结果证明了诱导型HSP 70在帮助加工和阻碍错误折叠的PMP 22积累方面的关键作用，这反过来又加剧了细胞内的蛋白毒性。
Chaperones, also called heat shock proteins (HSPs), transiently interact with proteins to aid their folding, trafficking, and degradation, thereby directly influencing the transport of newly synthesized molecules. Induction of chaperones provides a potential therapeutic approach for protein misfolding disorders, such as peripheral myelin protein 22 (PMP22)-associated peripheral neuropathies. Cytosolic aggregates of PMP22, linked with a demyelinating Schwann cell phenotype, result in suppression of proteasome activity and activation of proteostatic mechanisms, including the heat shock pathway. Although the beneficial effects of chaperones in preventing the aggregation and improving the trafficking of PMP22 have been repeatedly observed, the requirement for HSP70 in events remains elusive. In this study, we show that activation of the chaperone pathway in fibroblasts from PMP22 duplication-associated Charcot–Marie–Tooth disease type 1A patient with an FDA-approved small molecule increases HSP70 expression and attenuates proteasome dysfunction. Using cells from an HSP70.1/3−/− (inducible HSP70) mouse model, we demonstrate that under proteotoxic stress, this chaperone is critical in preventing the aggregation of PMP22, and this effect is aided by macroautophagy. When examined at steady-state, HSP70 appears to play a minor role in the trafficking of wild-type-PMP22, while it is crucial for preventing the buildup of the aggregation-prone Trembler-J-PMP22. HSP70 aids the processing of Trembler-J-PMP22 through the Golgi and its delivery to lysosomes via Rab7-positive vesicles. Together, these results demonstrate a key role for inducible HSP70 in aiding the processing and hindering the accumulation of misfolded PMP22, which in turn alleviates proteotoxicity within the cells.
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影响因子：
13.3
作者：
Finn, Patrick E.;Mesires, Nicholas T.;Dice, J. Fred
通讯作者：
Dice, J. Fred
影响因子：
4.8
作者：
Jinwal, Umesh K.;Akoury, Elias;Dickey, Chad A.
通讯作者：
Dickey, Chad A.
DOI：
10.1083/jcb.201110093
发表时间：
2012-03-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hipp MS;Patel CN;Bersuker K;Riley BE;Kaiser SE;Shaler TA;Brandeis M;Kopito RR
通讯作者：
Kopito RR
影响因子：
6.1
作者：
Fortun, Jenny;Verrier, Jonathan D.;Notterpek, Lucia
通讯作者：
Notterpek, Lucia
影响因子：
11.4
作者：
Liberek, Krzysztof;Lewandowska, Agnieszka;Zietkiewicz, Szymon
通讯作者：
Zietkiewicz, Szymon