Increased ER stress by depletion of PDIA6 impairs primary ciliogenesis and enhances sensitivity to ferroptosis in kidney cells

Joon Bum Kim, Hyejin Hyung, Ji Eun Bae, Soyoung Jang, Na Yeon Park, Doo Sin Jo, Yong Hwan Kim, Dong Kyu Choi, Hong Yeoul Ryu, Hyun Shik Lee, Zae Young Ryoo, Dong Hyung Cho

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)453-458
Number of pages6
JournalBMB Reports
Volume57
Issue number10
DOIs
StatePublished - 2024

Keywords

  • ER stress
  • Ferroptosis
  • HK-2 cells
  • PDIA6
  • Primary cilia

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