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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Increased ER stress by depletion of PDIA6 impairs primary ciliogenesis and enhances sensitivity to ferroptosis in kidney cells

  • Joon Bum Kim (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University) ;
  • Hyejin Hyung (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University) ;
  • Ji-Eun Bae (KNU LAMP Research Center, KNU Institute of Basic Sciences, Kyungpook National University) ;
  • Soyoung Jang (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University) ;
  • Na Yeon Park (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University) ;
  • Doo Sin Jo (ORGASIS Corp.) ;
  • Yong Hwan Kim (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University) ;
  • Dong Kyu Choi (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University) ;
  • Hong-Yeoul Ryu (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University) ;
  • Hyun-Shik Lee (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University) ;
  • Zae Young Ryoo (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University) ;
  • Dong-Hyung Cho (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University)
  • Received : 2023.12.26
  • Accepted : 2024.03.18
  • Published : 2024.10.31
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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 intensifies the ER stress response, while also impairing 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.

Keywords

Acknowledgement

This research was supported by the National Research Foundation of Korea, funded by the Ministry of Science & ICT (2020R1A2C2003523), and by Korea Institute for Advancement of Technology funded by the Ministry of Trade, Industry and Energy (P0025489). This research was supported by LAMP Program of the NRF grant funded by the Ministry of Education (RS-2023-00301914).

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