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울산대학교 의과대학, 서울아산병원

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Exp. Mol. Med., 18 July 2023 | https://doi.org/10.1038/s12276-023-01044-7 Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model

Jung-Eun Park ^{# 1}, Jiyoun Lee ^{# 2}, Soonhyuck Ok ¹, Seunghee Byun ¹, Eun-Ju Chang ^{3 4}, Sung-Eun Yoon ⁵, Young-Joon Kim ⁶, Min-Ji Kang ^{7 8 *}

¹Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
²School of Biopharmaceutical and Medical Sciences, Sungshin University, Seoul, 01133, Republic of Korea.
³Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
⁴Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
⁵Korea Drosophila Resource Center, Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, Republic of Korea.
⁶School of Life Sciences, Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, Republic of Korea.
⁷Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
⁸Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

#Contributed equally.
*Corresponding author: correspondence to Min-Ji Kang

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.

논문정보

형식Research article
게재일2023년 07월 (BRIC 등록일 2023-07-25)
연구진국내 연구진
분야 생명과학 > 분자생물학

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