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<p>The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. <i>Emp1</i> deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in <i>Emp1</i>-deficient HSCs and induce protein aggregation. Furthermore, <i>Emp1</i> deficiency renders HSCs more susceptible to IR, while overexpression of <i>Emp1</i> or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.</p>

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EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月7日

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  • Lei Li,
  • Yufei Lei,
  • Yan Li,
  • Yuxin Xie,
  • Pusheng Hui,
  • Xiaoyan Zang,
  • Weiru Wu,
  • Feng Wu,
  • Jiankun Fan,
  • Jianming Wang,
  • Jieping Chen,
  • Zhe Chen,
  • Yu Hou

摘要

The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in Emp1-deficient HSCs and induce protein aggregation. Furthermore, Emp1 deficiency renders HSCs more susceptible to IR, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.