Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response

• Published in: The Journal of biological chemistry 2024-12, p.108075, Article 108075
• Main Authors: Sasaki, Kanae, Toide, Marika, Adachi, Takuya, Morishita, Fumi, Watanabe, Yuto, Sakurai, Hajime Tajima, Wakabayashi, Sadao, Kusumi, Satoshi, Yamaji, Toshiyuki, Sakurai, Kaori, Koga, Daisuke, Hanada, Kentaro, Yohda, Masafumi, Yoshida, Hiderou
• Format: Article
• Language: English
• Subjects: cancer; Golgi stress response; OSW-1; phosphatidylinositol-4-phosphate; the Genome-wide CRISPR-Cas9 knockout screening
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2024.108075

The Golgi stress response is an important cytoprotective system that enhances Golgi function in response to cellular demand, while cells damaged by prolonged Golgi stress undergo cell death. OSW-1, a natural compound with anticancer activity, potently inhibits OSBP that transports cholesterol and phosphatidylinositol-4-phosphate (PI4P) at contact sites between the endoplasmic reticulum and the Golgi apparatus. Previously, we reported that OSW-1 induces the Golgi stress response, resulting in Golgi stress-induced transcription and cell death. However, the underlying molecular mechanism has been unknown. To reveal the mechanism of a novel pathway of the Golgi stress response regulating transcriptional induction and cell death (the PI4P pathway), we performed a genome-wide knockout screen and found that transcriptional induction as well as cell death induced by OSW-1 was repressed by the loss of regulators of PI4P synthesis, such as PITPNB and PI4KB. Our data indicate that OSW-1 induces Golgi stress-dependent transcriptional induction and cell death through dysregulation of the PI4P metabolism in the Golgi.