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Increased ER stress by depletion of PDIA6 impairs primary ciliogenesis and enhances sensitivity to ferroptosis in kidney cells.
Joon Bum Kim1,# (Graduate student), Hyejin Hyung1,# (Graduate student), Ji-Eun Bae2 (Research worker), Soyoung Jang1 (Research worker), Na Yeon Park1 (Research worker), Doo Sin Jo3 (Research worker), Yong Hwan Kim1 (Graduate student), Dong Kyu Choi1 (Professor), Hong-Yeoul Ryu1,2 (Professor), Hyun-Shik Lee1,2 (Professor), Zae Young Ryoo1 (Professor), Dong-Hyung Cho1,3,4,* (Professor)
1School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group and 2KNU LAMP Research Center, KNU Institute of Basic Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea,
3ORGASIS Corp. Suwon, Gyeonggi-do, 16229, Republic of Korea,
4Organelle Institute, Kyungpook National University, Daegu 41566, Republic of Korea
Abstract
Primary cilia are crucial for cellular balance, serving as sensors for external conditions. Nephronophthisis and related ciliopathies, which are hereditary and degenerative, stem from genetic mutations in cilia-related genes. However, the precise mechanisms of these conditions are still not fully understood. Our research demonstrates that downregulating PDIA6, leading to cilia removal, makes cells more sensitive to ferroptotic death caused by endoplasmic reticulum (ER) stress. The reduction of PDIA6 not only intensifies the ER stress response but also impairs the regulation of primary cilia in various cell types. PDIA6 loss worsens ER stress, hastening ferroptotic death in proximal tubule epithelial cells, HK2 cells. Counteracting this ER stress can mitigate PDIA6 depletion effects, restoring both the number and length of cilia. Moreover, preventing ferroptosis corrects the disrupted primary ciliogenesis due to PDIA6 depletion in HK2 cells. Our findings emphasize the role of PDIA6 in primary ciliogenesis and suggest its absence enhances ER stress and ferroptosis. These insights offer new therapeutic avenues for treating nephronophthisis and similar ciliopathies.
Abstract, Accepted Manuscript [Submitted on December 26, 2023, Accepted on March 18, 2024]
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