Scholarlink

<p>The mechanistic target of rapamycin complex 1 (mTORC1) is a central driver of cell growth that is frequently hyperactivated in cancer. While mTORC1 is activated at the lysosomal surface in response to growth factors and amino acids, the processes governing its inactivation are not fully understood. Here, we report that sustained mTORC1 suppression during leucine or arginine starvation requires the translocation of peripheral lysosomes to the perinuclear region. Our data suggest that a pool of mTOR remains active at peripheral lysosomes during starvation, and that increased spatial separation between lysosomes and the plasma membrane attenuates PI3K/Akt signaling—thereby reducing inputs that otherwise maintain mTORC1 activity. Consequently, preventing lysosome translocation and increasing peripheral lysosome levels sustains mTORC1 signaling during prolonged starvation in a PI3K/Akt-dependent manner independently of autophagy. Under these conditions, mTORC1 signaling persists even when lysosomal catabolism is perturbed by chloroquine or concanamycin A. Collectively, these data indicate that the peripheral lysosome pool, even when catabolically impaired, can sustain mTORC1 signaling under nutrient scarcity, by modulating PI3K/Akt signaling input to the pathway. These observations identify peripheral lysosome levels as a critical determinant of mTORC1 inactivation during nutrient stress and may have implications for diseases with aberrant mTORC1 signaling, including cancer.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月20日

查看全文
  • Huy Quang Dang,
  • Therése Forssén,
  • Spyridon Pantelios,
  • Aisegkioul Nteli Chatzioglou,
  • Ewa Kurzejamska,
  • C. Theresa Vincent,
  • Yasir Ibrahim,
  • Anders P. Mutvei

摘要

The mechanistic target of rapamycin complex 1 (mTORC1) is a central driver of cell growth that is frequently hyperactivated in cancer. While mTORC1 is activated at the lysosomal surface in response to growth factors and amino acids, the processes governing its inactivation are not fully understood. Here, we report that sustained mTORC1 suppression during leucine or arginine starvation requires the translocation of peripheral lysosomes to the perinuclear region. Our data suggest that a pool of mTOR remains active at peripheral lysosomes during starvation, and that increased spatial separation between lysosomes and the plasma membrane attenuates PI3K/Akt signaling—thereby reducing inputs that otherwise maintain mTORC1 activity. Consequently, preventing lysosome translocation and increasing peripheral lysosome levels sustains mTORC1 signaling during prolonged starvation in a PI3K/Akt-dependent manner independently of autophagy. Under these conditions, mTORC1 signaling persists even when lysosomal catabolism is perturbed by chloroquine or concanamycin A. Collectively, these data indicate that the peripheral lysosome pool, even when catabolically impaired, can sustain mTORC1 signaling under nutrient scarcity, by modulating PI3K/Akt signaling input to the pathway. These observations identify peripheral lysosome levels as a critical determinant of mTORC1 inactivation during nutrient stress and may have implications for diseases with aberrant mTORC1 signaling, including cancer.