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

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 knockou

SUBMITTER: Dr. Fabao Liu 

PROVIDER: S-SCDT-EMBOJ-2021-108065 | biostudies-other |

REPOSITORIES: biostudies-other