HSP70 promotes amino acid-dependent mTORC1 signaling by mediating CHIP-induced NPRL2 ubiquitination and degradation

FASEB J. 2024 Nov 15;38(21):e70147. doi: 10.1096/fj.202401352R.

Abstract

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.

Keywords: CHIP; HSP70; NPRL2; amino acid; mTORC1; ubiquitination.

MeSH terms

  • Amino Acids* / metabolism
  • Autophagy / physiology
  • Cell Proliferation
  • HEK293 Cells
  • HSP70 Heat-Shock Proteins* / genetics
  • HSP70 Heat-Shock Proteins* / metabolism
  • Humans
  • Mechanistic Target of Rapamycin Complex 1* / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Signal Transduction*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism
  • Ubiquitination*

Substances

  • Mechanistic Target of Rapamycin Complex 1
  • Ubiquitin-Protein Ligases
  • STUB1 protein, human
  • HSP70 Heat-Shock Proteins
  • NPRL2 protein, human
  • Amino Acids
  • Tumor Suppressor Proteins
  • Proteasome Endopeptidase Complex