Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, School of Life Sciences, Hunan Normal University, Changsha, Hunan, China.
FASEB J. 2024 Nov 15;38(21):e70147. doi: 10.1096/fj.202401352R.
Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and its dysregulation leads to a variety of human diseases. Although NPRL2, an essential component of the GATOR1 complex, is reported to effectively suppress amino acid-induced mTORC1 activation, the regulation of NPRL2 protein stability is unclear. In this study, we show that chaperon-associated ubiquitin ligase CHIP interacts with NPRL2 and promotes its polyubiquitination and proteasomal degradation. Moreover, HSP70 mediates CHIP-induced ubiquitination and degradation of NPRL2. Consistently, overexpression of HSP70 enhances whereas HSP70 depletion inhibits amino acid-induced mTORC1 activation. Accordingly, knockdown of HSP70 promotes basal autophagic flux, and inhibits cell growth and proliferation. Taken together, these results demonstrated that HSP70 is a novel activator of mTORC1 through mediating CHIP-induced ubiquitination and degradation of NPRL2.
雷帕霉素复合物 1 （mTORC1）的作用机制是细胞生长的主要调节因子，其失调会导致多种人类疾病。尽管 NPRL2 是 GATOR1 复合物的必需组成部分，据报道它能有效抑制氨基酸诱导的 mTORC1 激活，但 NPRL2 蛋白稳定性的调节尚不清楚。在这项研究中，我们表明伴侣相关泛素连接酶 CHIP 与 NPRL2 相互作用，并促进其多泛素化和蛋白酶体降解。此外，HSP70 介导 CHIP 诱导的 NPRL2 泛素化和降解。一致地，HSP70 的过表达增强了而 HSP70 的耗尽抑制了氨基酸诱导的 mTORC1 激活。因此，HSP70 的敲低促进了基础自噬通量，并抑制了细胞生长和增殖。总之，这些结果表明 HSP70 通过介导 CHIP 诱导的 NPRL2 泛素化和降解，成为 mTORC1 的新型激活剂。
