Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response
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 KO 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.
Authors
- Hiderou Yoshida (ORCID: https://orcid.org/0000-0002-5773-1408)
- Kaori Sakurai (ORCID: https://orcid.org/0000-0002-1348-8530)
- Hajime Tajima Sakurai (ORCID: https://orcid.org/0000-0001-7441-0203)
- Satoshi Kusumi (ORCID: https://orcid.org/0000-0002-4776-2956)
- Masafumi Yohda (ORCID: https://orcid.org/0000-0001-8307-9671)
- Kentaro Hanada (ORCID: https://orcid.org/0000-0003-1383-2781)
- Kanae Sasaki (ORCID: https://orcid.org/0000-0002-6630-3552)
- Daisuke Koga (ORCID: https://orcid.org/0000-0002-2792-7207)
- Toshiyuki Yamaji (ORCID: https://orcid.org/0000-0002-4251-489X)
- Yuto Watanabe
- Marika Toide
- Takuya Adachi
- Sadao Wakabayashi
- Fumi Morishita
Institutions
- Kagoshima University (JP)
- Asahikawa Medical University (JP)
- University of Hyogo (JP)
- Juntendo University (JP)
- National Institute of Infectious Diseases (JP)
- Hyogo University (JP)
- Tokyo University of Agriculture and Technology (JP)
Publication Details
- Journal
- Journal of Biological Chemistry
- Published
- 2024-12-13
- DOI
- https://doi.org/10.1016/j.jbc.2024.108075
- Citations
- 6
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 1.96
Funders
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Foundation of Kinoshita Memorial Enterprise
- Ministry of Education, Culture, Sports, Science and Technology
- Tokyo Medical and Dental University
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology