PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controlling SCAP stability

EMBO J. 2021 Nov 15;40(22):e108065. doi: 10.15252/embj.2021108065. Epub 2021 Sep 6.


The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer cells to regulate anabolic metabolism. Although PKM2 was recently reported to regulate lipid homeostasis, the molecular mechanism remains unclear. Herein, we discovered an ER transmembrane protein 33 (TMEM33) as a downstream effector of PKM2 that regulates activation of SREBPs and lipid metabolism. Loss of PKM2 leads to up-regulation of TMEM33, which recruits RNF5, an E3 ligase, to promote SREBP-cleavage activating protein (SCAP) degradation. TMEM33 is transcriptionally regulated by nuclear factor erythroid 2-like 1 (NRF1), whose cleavage and activation are controlled by PKM2 levels. Total plasma cholesterol levels are elevated by either treatment with PKM2 tetramer-promoting agent TEPP-46 or by global PKM2 knockout in mice, highlighting the essential function of PKM2 in lipid metabolism. Although depletion of PKM2 decreases cancer cell growth, global PKM2 knockout accelerates allografted tumor growth. Together, our findings reveal the cell-autonomous and systemic effects of PKM2 in lipid homeostasis and carcinogenesis, as well as TMEM33 as a bona fide regulator of lipid metabolism.

Keywords: PKM2; SCAP degradation; TMEM33; total cholesterol levels; tumor growth.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cholesterol / blood
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homeostasis
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipid Metabolism / physiology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • Xenograft Model Antitumor Assays


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SREBF1 protein, human
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Protein 1
  • Thyroid Hormones
  • Tmem33 protein, mouse
  • transmembrane protein 33, human
  • Cholesterol