Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology
Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology
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DOI：
10.1038/nature08710
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发表时间：
2010-01-28
期刊：
影响因子：
64.8
通讯作者：
Jaattela, Marja
中科院分区：
文献类型：
--
作者：
Kirkegaard, Thomas;Roth, Anke G.;Jaattela, Marja
热休克蛋白70 （Hsp70）是一种进化上高度保守的分子伴侣，通过抑制溶酶体膜通透性来促进应激细胞的存活（1-5），这是应激诱导细胞死亡的标志（6-10）。其分子作用机制的线索可能在于最近报道的应激和癌症相关的一小部分Hsp70向溶酶体腔室的易位（1,11）。在这里，我们发现Hsp70通过结合内溶酶体阴离子磷脂（单酰基甘油）磷酸（BMP）来稳定溶酶体，BMP是溶酶体鞘磷脂代谢的重要辅助因子（12-14）。在酸性环境中，Hsp70以高亲和力和特异性结合BMP，从而促进BMP的结合和酸性鞘磷脂酶（ASM）的活性。BMP抗体或Hsp70点突变（Trp90Phe）抑制Hsp70-BMP相互作用，以及ASM的药理学和遗传抑制，有效地恢复了Hsp70介导的溶酶体稳定。值得注意的是，由编码ASM的鞘磷脂二酯酶1基因（SMPD1）突变引起的neemann - pick病（NPD） A和b患者细胞中ASM活性降低（15）也与溶酶体稳定性显著降低相关，这种表型可以通过重组Hsp70治疗有效纠正。综上所述，这些数据为开发溶酶体储存障碍和癌症的新治疗方法提供了令人兴奋的可能性，这些化合物通过内吞传递途径进入溶酶体腔。
Heat shock protein 70 (Hsp70) is an evolutionarily highly conserved molecular chaperone that promotes the survival of stressed cells by inhibiting lysosomal membrane permeabilization(1-5), a hallmark of stress-induced cell death(6-10). Clues to its molecular mechanism of action may lay in the recently reported stress-and cancer-associated translocation of a small portion of Hsp70 to the lysosomal compartment(1,11). Here we show that Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero) phosphate (BMP), an essential co-factor for lysosomal sphingomyelin metabolism(12-14). In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of acid sphingomyelinase (ASM). The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (Trp90Phe), as well as the pharmacological and genetic inhibition of ASM, effectively revert the Hsp70-mediated stabilization of lysosomes. Notably, the reduced ASM activity in cells from patients with Niemann-Pick disease (NPD) A and B-severe lysosomal storage disorders caused by mutations in the sphingomyelin phosphodiesterase 1 gene (SMPD1) encoding for ASM(15)-is also associated with a marked decrease in lysosomal stability, and this phenotype can be effectively corrected by treatment with recombinant Hsp70. Taken together, these data open exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway.