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PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controlling SCAP stability.
- Source :
-
The EMBO journal [EMBO J] 2021 Nov 15; Vol. 40 (22), pp. e108065. Date of Electronic Publication: 2021 Sep 06. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2021 The Authors.)
- Subjects :
- Animals
Breast Neoplasms genetics
Breast Neoplasms metabolism
Carrier Proteins genetics
Cell Line, Tumor
Cholesterol blood
Female
Gene Expression Regulation, Neoplastic
Homeostasis
Humans
Intracellular Signaling Peptides and Proteins genetics
Membrane Proteins genetics
Mice, Knockout
Sterol Regulatory Element Binding Protein 1 metabolism
Thyroid Hormones genetics
Xenograft Model Antitumor Assays
Thyroid Hormone-Binding Proteins
Mice
Carrier Proteins metabolism
Intracellular Signaling Peptides and Proteins metabolism
Lipid Metabolism physiology
Membrane Proteins metabolism
Thyroid Hormones metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2075
- Volume :
- 40
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 34487377
- Full Text :
- https://doi.org/10.15252/embj.2021108065