Formation of giant ER sheets by pentadecanoic acid causes lipotoxicity in fission yeast

• 成果类型: Article
• 署名作者: Hoshikawa, Yojiro; Shirota, Natsuho; Tsugawa, Hiroshi; Kimura, Satoshi; Matsuyama, Akihisa; Yashiroda, Yoko; Kakeya, Hideaki; Arita, Makoto; Iizumi, Reiko; Yoshida, Minoru; Nishimura, Shinichi
• 署名单位: University of Tokyo; Hiroshima University; Hiroshima University; RIKEN; RIKEN; Yokohama City University; Tokyo University of Agriculture & Technology; University of Tokyo; RIKEN; Kyoto University; Keio University; Keio University; University of California System; University of California San Diego; Scripps Institution of Oceanography; University of Tokyo; University of Tokyo; RIKEN
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12690
• DOI: 10.1073/pnas.2422126122
• 发表日期: 2025-06-03
• 关键词: coa synthetase gene; endoplasmic-reticulum; membrane-proteins; stationary-phase; fatty-acids; cells; entry; morphology; EFFICIENCY; ergosterol

摘要

Excess amounts of saturated fatty acids (FAs) are toxic to organisms, a condition termed lipotoxicity, which is often accompanied by pleiotropic cellular and tissue dysfunction. Here, we show that pentadecanoic acid (C15:0) exerts toxicity on the fission yeast Schizosaccharomyces pombe by generating an aberrantly planar endoplasmic reticulum (ER) structure, which we named a giant ER sheet. Untargeted lipidomics revealed that C15:0 is incorporated into complex lipids depending on an acyl- CoA ligase Lcf1 and an acyl- CoA transferase Slc1, thereby increasing the saturation level of the acyl chains. The toxicity and giant ER sheet formation were abolished by deleting lcf1 or slc1 gene, indicating that the incorporation of C15:0 into glycerophospholipids causes giant ER sheet formation. The giant ER sheets disrupted the correct migration of Mid1, a protein determining the cell division site, and physically blocked septum formation, hindering correct cell separation. Our results suggest that the ER is the primary site targeted by saturated FAs, leading to lipotoxicity.