HSP90α is needed for the survival of rod photoreceptors and regulates the expression of rod PDE6 subunits.
HSP90α is needed for the survival of rod photoreceptors and regulates the expression of rod PDE6 subunits.
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DOI：
10.1016/j.jbc.2023.104809
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发表时间：
2023-06
影响因子：
4.8
通讯作者：
Ramamurthy, Visvanathan
中科院分区：
文献类型：
--
作者：
Munezero, Daniella;Aliff, Hunter;Salido, Ezequiel;Saravanan, Thamaraiselvi;Sanzhaeva, Urikhan;Guan, Tongju;Ramamurthy, Visvanathan
热休克蛋白90（HSP 90）是一种丰富的分子伴侣，调节一小部分在各种细胞途径中必不可少的蛋白质的稳定性。胞质HSP 90有两个密切相关的旁系同源物：HSP 90 α和HSP 90 β。由于胞质HSP 90旁系同源物的结构和序列相似性，鉴定细胞中的独特功能和底物仍然具有挑战性。在这篇文章中，我们评估了HSP 90 α在视网膜中的作用，使用一种新的HSP 90 α基因敲除小鼠模型。我们的研究结果表明HSP 90 α对视杆细胞的功能是必需的，而在视锥细胞中则被抑制。在缺乏HSP 90 α的情况下，光感受器正常发育。我们观察到HSP 90 α基因敲除组在2个月时出现视杆细胞功能障碍，出现空泡结构、凋亡核和外节异常。视杆细胞功能的下降伴随着视杆细胞光感受器的进行性退化，在6个月时完全退化。视锥细胞功能和健康的恶化是视杆细胞变性后的“旁观者效应”。串联质量标签蛋白质组学研究表明，HSP 90 α调控的视网膜蛋白质组表达水平<1%。更重要的是，HSP 90 α在维持视杆细胞中PDE 6和AIPL 1辅伴侣蛋白水平方面至关重要。有趣的是，锥PDE 6水平不受影响。视锥细胞中HSP 90 β的稳定表达可能弥补了HSP 90 α的缺失。总之，我们的研究证明了在视杆细胞的维持中对HSP 90 α分子伴侣的关键需求，并显示了视网膜中HSP 90 α调节的潜在底物。
Heat shock protein 90 (HSP90) is an abundant molecular chaperone that regulates the stability of a small set of proteins essential in various cellular pathways. Cytosolic HSP90 has two closely related paralogs: HSP90α and HSP90β. Due to the structural and sequence similarities of cytosolic HSP90 paralogs, identifying the unique functions and substrates in the cell remains challenging. In this article, we assessed the role of HSP90α in the retina using a novel HSP90α murine knockout model. Our findings show that HSP90α is essential for rod photoreceptor function but was dispensable in cone photoreceptors. In the absence of HSP90α, photoreceptors developed normally. We observed rod dysfunction in HSP90α knockout at 2 months with the accumulation of vacuolar structures, apoptotic nuclei, and abnormalities in the outer segments. The decline in rod function was accompanied by progressive degeneration of rod photoreceptors that was complete at 6 months. The deterioration in cone function and health was a “bystander effect” that followed the degeneration of rods. Tandem mass tag proteomics showed that HSP90α regulates the expression levels of <1% of the retinal proteome. More importantly, HSP90α was vital in maintaining rod PDE6 and AIPL1 cochaperone levels in rod photoreceptor cells. Interestingly, cone PDE6 levels were unaffected. The robust expression of HSP90β paralog in cones likely compensates for the loss of HSP90α. Overall, our study demonstrated the critical need for HSP90α chaperone in the maintenance of rod photoreceptors and showed potential substrates regulated by HSP90α in the retina.