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

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주제분류화학

초록

Primary cilia are crucial for cellular balance, serving as sensorsfor external conditions. Nephronophthisis and related ciliopathies,which are hereditary and degenerative, stem from geneticmutations in cilia-related genes. However, the precise mechanismsof these conditions are still not fully understood. Ourresearch demonstrates that downregulating PDIA6, leading tocilia removal, makes cells more sensitive to ferroptotic deathcaused by endoplasmic reticulum (ER) stress. The reduction ofPDIA6 intensifies the ER stress response, while also impairingthe regulation of primary cilia in various cell types. PDIA6 lossworsens ER stress, hastening ferroptotic death in proximal tubuleepithelial cells, HK2 cells. Counteracting this ER stress canmitigate PDIA6 depletion effects, restoring both the number andlength of cilia. Moreover, preventing ferroptosis corrects thedisrupted primary ciliogenesis due to PDIA6 depletion in HK2cells. Our findings emphasize the role of PDIA6 in primaryciliogenesis, and suggest its absence enhances ER stress andferroptosis. These insights offer new therapeutic avenues fortreating nephronophthisis and similar ciliopathies.

Abstract

Primary cilia are crucial for cellular balance, serving as sensorsfor external conditions. Nephronophthisis and related ciliopathies,which are hereditary and degenerative, stem from geneticmutations in cilia-related genes. However, the precise mechanismsof these conditions are still not fully understood. Ourresearch demonstrates that downregulating PDIA6, leading tocilia removal, makes cells more sensitive to ferroptotic deathcaused by endoplasmic reticulum (ER) stress. The reduction ofPDIA6 intensifies the ER stress response, while also impairingthe regulation of primary cilia in various cell types. PDIA6 lossworsens ER stress, hastening ferroptotic death in proximal tubuleepithelial cells, HK2 cells. Counteracting this ER stress canmitigate PDIA6 depletion effects, restoring both the number andlength of cilia. Moreover, preventing ferroptosis corrects thedisrupted primary ciliogenesis due to PDIA6 depletion in HK2cells. Our findings emphasize the role of PDIA6 in primaryciliogenesis, and suggest its absence enhances ER stress andferroptosis. These insights offer new therapeutic avenues fortreating nephronophthisis and similar ciliopathies.

참고문헌 (41)

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