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

• Published in: The EMBO journal 2021-11, Vol.40 (22), p.e108065-n/a
• Main Authors: Liu, Fabao, Ma, Min, Gao, Ang, Ma, Fengfei, Ma, Gui, Liu, Peng, Jia, Chenxi, Wang, Yidan, Donahue, Kristine, Zhang, Shengjie, Ong, Irene M, Keles, Sunduz, Li, Lingjun, Xu, Wei
• Format: Article
• Language: English
• Subjects: Animals; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Carcinogenesis; Carcinogens; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; Cholesterol; Cholesterol - blood; Cleavage; Control stability; Degradation; Depletion; EMBO03; EMBO21; EMBO37; Endoplasmic reticulum; Female; Gene Expression Regulation, Neoplastic; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Lipid metabolism; Lipid Metabolism - physiology; Lipids; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolism; Mice; Mice, Knockout; PKM2; Proteins; Pyruvate kinase; Pyruvic acid; SCAP degradation; Sterol Regulatory Element Binding Protein 1 - metabolism; Sterol regulatory element-binding protein; Therapeutic applications; Thyroid Hormone-Binding Proteins; Thyroid Hormones - genetics; Thyroid Hormones - metabolism; TMEM33; total cholesterol levels; tumor growth; Tumors; Ubiquitin-protein ligase; Ubiquitination; Xenograft Model Antitumor Assays
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2021108065

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. SYNOPSIS This study identifies the endoplasmic reticulum (ER) transmembrane protein TMEM33 as a new mechanistic target of pyruvate kinase M2 (PKM2) and bona fide regulator of lipid metabolism. These findings have implications for cancer caused by elevated plasma cholesterol levels and underscore systemic functions of PKM2, opening up new avenues for therapeutic interventions. PKM2 down‐regulates TMEM33 expression in MEFs and breast cancer cells, derepressing the lipogenic transcription factor SREBP. TMEM33 is transcriptionally regulated by NRF1, whose activation depends on the PKM2/VCP axis. PKM2 loss induces TMEM33, leading it to recruit E3 ligase RNF5 for ubiquitination and degradation of SREBP‐cleavage factor SCAP. Depletion of PKM2 in mice elevates global cholesterol levels and promotes allografted growth of hepatocellular cancer. Graphical Abstract Transmembrane protein TMEM33 is a novel target of ER‐localised PKM2 and regulator of cholesterol metabolism.