The molecular chaperone Hsp90α deficiency causes retinal degeneration by disruption of Golgi organization and vesicle transport in photoreceptors
The molecular chaperone Hsp90α deficiency causes retinal degeneration by disruption of Golgi organization and vesicle transport in photoreceptors
复制标题
分子伴侣 Hsp90α 缺陷通过破坏光感受器中的高尔基组织和囊泡运输而导致视网膜变性
DOI：
10.1093/jmcb/mjz048
复制
发表时间：
2019
影响因子：
5.5
通讯作者：
Kan Liao
中科院分区：
文献类型：
--
作者：
Yuan Wu;Xiudan Zheng;Yubo Ding;Min Zhou;Zhuang Wei;Tao Liu;Kan Liao
热休克蛋白90（Heat shock protein 90，Hsp 90）是一种丰富的分子伴侣蛋白，有两种异构体：Hsp 90 α和Hsp 90 β。Hsp 90 β缺陷导致胚胎死亡，而Hsp 90 α缺陷导致除雄性不育外的少数异常。本文报道了Hsp 90 α仅在视网膜、睾丸和脑中表达。它的缺乏引起视网膜色素变性（RP），一种导致失明的疾病。Hsp 90 α基因缺陷小鼠视网膜退化，光感受器外节变形。免疫荧光染色和电子显微镜分析显示，在Hsp 90 α缺陷的光感受器中，高尔基体解体，节段间囊泡运输异常。蛋白质组学分析鉴定微管相关蛋白1B（MAP 1B）为光感受器中的Hsp 90 α相关蛋白。Hspα缺陷通过诱导MAP 1B的泛素化，导致α-微管蛋白脱乙酰化和微管不稳定，从而增加MAP 1B的降解。此外，用格尔德霉素衍生物的Hsp 90抑制剂17-DMAG治疗野生型小鼠，诱导与Hsp 90 α缺乏相同的视网膜变性。因此，微管不稳定可能是Hsp 90 α缺陷诱导RP的根本原因。
Heat shock protein 90 (Hsp90) is an abundant molecular chaperone with two isoforms, Hsp90αand Hsp90β. Hsp90βdeficiency causes embryonic lethality, whereas Hsp90αdeficiency causes few abnormities except male sterility. In this paper, we reported that Hsp90αwas exclusively expressed in the retina, testis, and brain. Its deficiency caused retinitis pigmentosa (RP), a disease leading to blindness. In Hsp90α-deficient mice, the retina was deteriorated and the outer segment of photoreceptor was deformed. Immunofluorescence staining and electron microscopic analysis revealed disintegrated Golgi and aberrant intersegmental vesicle transportation in Hsp90α-deficient photoreceptors. Proteomic analysis identified microtubule-associated protein 1B (MAP1B) as an Hsp90α-associated protein in photoreceptors. Hspαdeficiency increased degradation of MAP1B by inducing its ubiquitination, causingα-tubulin deacetylation and microtubule destabilization. Furthermore, the treatment of wild-type mice with 17-DMAG, an Hsp90 inhibitor of geldanamycin derivative, induced the same retinal degeneration as Hsp90αdeficiency. Taken together, the microtubule destabilization could be the underlying reason for Hsp90αdeficiency-induced RP.