Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model

Abstract

The endoplasmic reticulum (ER) is a subcellular organelle essential for cellular homeostasis. Perturbation of ER functions due to various conditions can induce apoptosis. Chronic ER stress has been implicated in a wide range of diseases, including autosomal dominant retinitis pigmentosa (ADRP), which is characterized by age-dependent retinal degeneration caused by mutant rhodopsin alleles. However, the signaling pathways that mediate apoptosis in response to ER stress remain poorly understood. In this study, we performed an unbiased in vivo RNAi screen with a Drosophila ADRP model and found that Wg/Wnt1 mediated apoptosis. Subsequent transcriptome analysis revealed that ER stress-associated serine protease (Erasp), which has been predicted to show serine-type endopeptidase activity, was a downstream target of Wg/Wnt1 during ER stress. Furthermore, knocking down Erasp via RNAi suppressed apoptosis induced by mutant rhodopsin-1 (Rh-1^P37H) toxicity, alleviating retinal degeneration in the Drosophila ADRP model. In contrast, overexpression of Erasp resulted in enhanced caspase activity in Drosophila S2 cells treated with apoptotic inducers and the stabilization of the initiator caspase Dronc (Death regulator Nedd2-like caspase) by stimulating DIAP1 (Drosophila inhibitor of apoptosis protein 1) degradation. These findings helped identify a novel cell death signaling pathway involved in retinal degeneration in an autosomal dominant retinitis pigmentosa model.

Eye disease: a pathway to cell death in retinitis pigmentosa

A Drosophila fly model of an inherited form of the eye disease retinitis pigmentosa has revealed a signaling and control pathway involving the intracellular endoplasmic reticulum structure that leads to cell death. Retinitis pigmentosa is an age-related disease of the retina of the eye, leading to progressive vision loss. It is known to involve dysfunction of the endoplasmic reticulum, which, among other functions crucial for cell health, is essential for the synthesis of many proteins. Researchers in South Korea led by Min-Ji Kang at the University of Ulsan College of Medicine identified specific genes and proteins involved in their Drosophila model of RP, which may also be significant in human disease. These insights may contribute to preventing the progression of retinitis pigmentosa in human patients.