Biozentrum, University of Basel, Basel 4056, Switzerland.
Proc Natl Acad Sci U S A. 2024 Aug 20;121(34):e2405959121. doi: 10.1073/pnas.2405959121. Epub 2024 Aug 14.
TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, understanding mTORC1 downstream signaling and feedback loops is important. mTORC1 recognizes some of its substrates via a five amino acid binding sequence called the TOR signaling (TOS) motif. mTORC1 binding to a TOS motif facilitates phosphorylation of a distinct, distal site. Here, we show that LST2, also known as ZFYVE28, contains a TOS motif (amino acids 401 to 405) and is directly phosphorylated by mTORC1 at serine 670 (S670). mTORC1-mediated S670 phosphorylation promotes LST2 monoubiquitination on lysine 87 (K87). Monoubiquitinated LST2 is stable and displays a broad reticular distribution. When mTORC1 is inactive, unphosphorylated LST2 is degraded by the proteasome. The absence of LST2 enhances EGFR (epidermal growth factor receptor) signaling. We propose that mTORC1 negatively feeds back on its upstream receptor EGFR via LST2.
TORC1（雷帕霉素复合物 1 靶标）是一种高度保守的蛋白激酶，在调节细胞生长中起着核心作用。鉴于哺乳动物 TORC1（mTORC1）在代谢和疾病中的作用，理解 mTORC1 下游信号转导和反馈回路非常重要。mTORC1 通过称为 TOR 信号（TOS）基序的五个氨基酸结合序列识别其一些底物。mTORC1 与 TOS 基序的结合促进了独特的、远端位点的磷酸化。在这里，我们表明，LST2，也称为 ZFYVE28，含有一个 TOS 基序（氨基酸 401 到 405），并被 mTORC1 在丝氨酸 670（S670）处直接磷酸化。mTORC1 介导的 S670 磷酸化促进 LST2 在赖氨酸 87（K87）上的单泛素化。单泛素化的 LST2 是稳定的，并显示出广泛的网状分布。当 mTORC1 不活跃时，未磷酸化的 LST2 被蛋白酶体降解。LST2 的缺失增强了 EGFR（表皮生长因子受体）信号。我们提出，mTORC1 通过 LST2 负反馈其上游受体 EGFR。
