Chronic endoplasmic reticulum (ER) stress is the underlying cause of many degenerative diseases, including autosomal dominant retinitis pigmentosa (adRP). In adRP, mutant rhodopsins accumulate and cause ER stress. This destabilizes wild-type rhodopsin and triggers photoreceptor cell degeneration. To reveal the mechanisms by which these mutant rhodopsins exert their dominant-negative effects, we established an in vivo fluorescence reporter system to monitor mutant and wild-type rhodopsin in Drosophila. By performing a genome-wide genetic screen, we found that PERK signaling plays a key role in maintaining rhodopsin homeostasis by attenuating IRE1 activities. Degradation of wild-type rhodopsin is mediated by selective autophagy of ER, which is induced by uncontrolled IRE1/XBP1 signaling and insufficient proteasome activities. Moreover, upregulation of PERK signaling prevents autophagy and suppresses retinal degeneration in the adRP model. These findings establish a pathological role for autophagy in this neurodegenerative condition and indicate that promoting PERK activity could be used to treat ER stress-related neuropathies, including adRP.

中文翻译：

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PERK 通过抑制 IRE1 诱导的自噬来防止色素性视网膜炎期间视紫红质的降解

慢性内质网（ER）应激是许多退行性疾病的根本原因，包括常染色体显性视网膜色素变性（adRP）。在 adRP 中，突变视紫红质积累并引起 ER 应激。这会破坏野生型视紫红质的稳定性并引发感光细胞变性。为了揭示这些突变型视紫红质发挥显性负效应的机制，我们建立了体内荧光报告系统来监测果蝇中的突变型和野生型视紫红质。通过进行全基因组遗传筛选，我们发现 PERK 信号通过减弱 IRE1 活性在维持视紫红质稳态中发挥关键作用。野生型视紫红质的降解是由 ER 的选择性自噬介导的，这是由不受控制的 IRE1/XBP1 信号传导和蛋白酶体活性不足诱导的。此外，在 adRP 模型中，PERK 信号传导的上调可防止自噬并抑制视网膜变性。这些发现确立了自噬在这种神经退行性疾病中的病理作用，并表明促进 PERK 活性可用于治疗 ER 应激相关的神经病，包括 adRP。