Membrane-lipid therapy in operation: the HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts.
Membrane-lipid therapy in operation: the HSP co-inducer BGP-15 activates stress signal transduction pathways by remodeling plasma membrane rafts.
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DOI：
10.1371/journal.pone.0028818
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Vígh L
中科院分区：
文献类型：
--
作者：
Gombos I;Crul T;Piotto S;Güngör B;Török Z;Balogh G;Péter M;Slotte JP;Campana F;Pilbat AM;Hunya A;Tóth N;Literati-Nagy Z;Vígh L Jr;Glatz A;Brameshuber M;Schütz GJ;Hevener A;Febbraio MA;Horváth I;Vígh L
衰老和病理生理条件与膜的变化有关，膜控制的分子开关，导致热休克蛋白(HSP)的异常表达。热休克蛋白联合诱导剂羟胺，如BGP-15，为许多疾病提供了先进的治疗候选药物，因为它们优先影响应激细胞，不太可能有重大副作用。在目前的研究中，体外分子动力学模拟、脂质单层实验和体内超灵敏荧光显微镜实验表明，BGP-15改变了富含胆固醇的膜域的组织结构。使用RAFT标记糖基磷脂酰肌醇锚定的单体绿色荧光蛋白在活的中国仓鼠卵巢(CHO)细胞质膜中扩散的纳米级长寿命平台的成像表明，BGP-15防止了发热型热应激导致的筏子的瞬时结构解体。此外，BGP-15能够重塑富含胆固醇的脂质平台，这让人想起早先在非致命性热启动或膜应激后观察到的情况，并被证明是产生和传递应激信号的专职。BGP-15激活B16-F10小鼠黑色素瘤细胞中HSP的表达涉及rac1信号级联反应，这与先前的观察结果一致，即胆固醇影响rac1对膜的靶向。最后，在人类胚胎肾细胞系中，我们证明了BGP-15能够抑制在热应激早期监测到的快速热休克因子1(HSF1)乙酰化，从而促进HSF1与热休克元件结合的持续时间延长。综上所述，我们的结果表明，BGP-15有可能成为一类新的药物，用于膜脂疗法，以对抗许多与衰老相关的各种蛋白质错误折叠疾病。
Aging and pathophysiological conditions are linked to membrane changes which modulate membrane-controlled molecular switches, causing dysregulated heat shock protein (HSP) expression. HSP co-inducer hydroxylamines such as BGP-15 provide advanced therapeutic candidates for many diseases since they preferentially affect stressed cells and are unlikely have major side effects. In the present study in vitro molecular dynamic simulation, experiments with lipid monolayers and in vivo ultrasensitive fluorescence microscopy showed that BGP-15 alters the organization of cholesterol-rich membrane domains. Imaging of nanoscopic long-lived platforms using the raft marker glycosylphosphatidylinositol-anchored monomeric green fluorescent protein diffusing in the live Chinese hamster ovary (CHO) cell plasma membrane demonstrated that BGP-15 prevents the transient structural disintegration of rafts induced by fever-type heat stress. Moreover, BGP-15 was able to remodel cholesterol-enriched lipid platforms reminiscent of those observed earlier following non-lethal heat priming or membrane stress, and were shown to be obligate for the generation and transmission of stress signals. BGP-15 activation of HSP expression in B16-F10 mouse melanoma cells involves the Rac1 signaling cascade in accordance with the previous observation that cholesterol affects the targeting of Rac1 to membranes. Finally, in a human embryonic kidney cell line we demonstrate that BGP-15 is able to inhibit the rapid heat shock factor 1 (HSF1) acetylation monitored during the early phase of heat stress, thereby promoting a prolonged duration of HSF1 binding to heat shock elements. Taken together, our results indicate that BGP-15 has the potential to become a new class of pharmaceuticals for use in ‘membrane-lipid therapy’ to combat many various protein-misfolding diseases associated with aging.
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DOI：
10.1016/j.bbalip.2010.04.011
发表时间：
2010-09-01
影响因子：
4.8
作者：
Balogh, Gabor;Peter, Maria;Vigh, Laszlo
通讯作者：
Vigh, Laszlo
影响因子：
5.3
作者：
Cerezo, Ana;Guadamillas, Marta C.;del Pozo, Miguel A.
通讯作者：
del Pozo, Miguel A.
影响因子：
2.4
作者：
Kucerka, N;Tristram-Nagle, S;Nagle, JF
通讯作者：
Nagle, JF
影响因子：
5.3
作者：
Escribá PV;González-Ros JM;Goñi FM;Kinnunen PK;Vigh L;Sánchez-Magraner L;Fernández AM;Busquets X;Horváth I;Barceló-Coblijn G
通讯作者：
Barceló-Coblijn G
影响因子：
2.9
作者：
Krieger, E;Darden, T;Vriend, G
通讯作者：
Vriend, G