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KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing

Jie Chen1,2, Yuhui Ou1, Yanyan Yang1

  • 1State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.

Nature
|May 18, 2018
PubMed

Insights

The CUL3-KLHL22 ligase degrades DEPDC5 to activate mTORC1 signaling in response to amino acids. This mechanism is crucial for cell growth and has implications for treating cancer and age-related diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and responds to amino acids.
  • Deregulation of mTORC1 is implicated in metabolic diseases, cancer, and aging.
  • The GATOR1 complex inhibits mTORC1 activation by targeting Rag GTPases under low amino acid conditions.

Purpose of the Study:

  • To elucidate the mechanism by which GATOR1's inhibitory function is released upon amino acid stimulation.
  • To investigate the role of the CUL3-KLHL22 E3 ubiquitin ligase in mTORC1 activation.

Main Methods:

  • Investigated the interaction between CUL3-KLHL22 and DEPDC5.
  • Analyzed the ubiquitination and degradation of DEPDC5.
  • Studied the role of KLHL22 in Caenorhabditis elegans lifespan.
  • Examined KLHL22 and DEPDC5 levels in human breast cancer tissues and cell lines.
  • Assessed the effect of KLHL22 depletion on tumor growth in mice.

Main Results:

  • CUL3-KLHL22 ligase mediates K48-linked polyubiquitination and degradation of DEPDC5 upon amino acid stimulation.
  • KLHL22 is essential for mTORC1 activation and downstream events in mammals and nematodes.
  • Depletion of the C. elegans orthologue MEL-26 extends worm lifespan.
  • Elevated KLHL22 and reduced DEPDC5 levels are observed in breast tumors.
  • KLHL22 depletion suppresses breast cancer cell growth in vivo.

Conclusions:

  • The CUL3-KLHL22-DEPDC5 axis is a key regulator of mTORC1 activation in response to amino acids.
  • KLHL22 plays a critical role in promoting cell growth and is implicated in cancer.
  • Targeting KLHL22 may offer therapeutic strategies for breast cancer and age-related diseases.

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