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 2like 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.

LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation

“…Sterol regulatory element-binding proteins (SREBPs, also known as SREB factors/SREBFs, encoded by Srebf genes) are pivotal transcription factors that respond to low sterol concentrations and regulate cellular lipid metabolism ( Liu F. et al, 2021 ; Xu Y. et al, 2021 ). SREBPs have also been reported to be hijacked for replication by multiple viruses ( Martín-Acebes et al, 2019 ; Cloherty et al, 2020 ; Tanner and Alfieri, 2021 ).…”

“…Under cholesterol-depleted conditions, SREBP cleavage-activating proteins (SCAPs) are stimulated to escort SREBP2 from the endoplasmic reticulum (ER) membrane to the Golgi, where SREBP2 undergoes proteolytic cleavage in multiple steps to release the ∼480 amino acid NH 2 -terminal domain (N-SREBP2). N-SREBP2 is a mature, biologically active peptide that translocates into the nucleus, binds to sterol regulatory elements (SREs), and activates its canonical target genes (such as 7-dehydrocholesterol reductase / Dhcr7 and squalene epoxidase/Sqle ) to promote cholesterol biosynthesis ( Liu F. et al, 2021 ; Xu Y. et al, 2021 ). Recent studies revealed that SREB2 could not only promote NLRP3 inflammasome activation but also directly bind to inflammatory genes and trigger their expression, ultimately stimulating M1-type macrophages ( Guo et al, 2018 ; Kusnadi et al, 2019 ).…”

Lipid metabolism: new twists to the Yin and Yang of PKM2 in cancer

“…Notably, Liu et al (2021) report an additional layer of complexity in PKM2 function by identifying the mechanism by which PKM2 contributes to lipid homeostasis (Fig 1). PKM2 was shown before to control the sterol regulatory element‐binding proteins (SREBPs), the key transcription factors controlling lipogenesis and lipid uptake (Zhao et al , 2018) and to suppress hepatic steatosis in liver cancer models (Dayton et al , 2016b), but the molecular underpinnings for these functions remained unclear.…”

“…In line with SCAP’s requirement for SREBP1 nuclear localization and transactivation of lipogenic gene transcription (Brown et al , 2018), loss of PKM2 in these cells resulted in attenuated expression of lipid synthetic genes. Liu et al (2021) also demonstrated that the increase in TMEM33 expression resulting from PKM2 loss was mediated by the transcription factor NRF1, whose cleavage and activation depend on the activity of valosin‐containing protein (VCP) and PKM2 at the ER membrane.…”

“…A number of questions remain about the tissue‐specific functions of PKM2 in this context. It will be of interest to see a systematic evaluation of the key players identified by Liu et al (2021) including NRF1, TMEM33, and RNF5, in different organs/tissues of the PKM2 KO mice. Likewise, transgenic mouse models that carry PKM2 mutations detected in human cancers could help to identify tissue‐specific changes that distinguish between canonical and non‐canonical pathways linked to PKM2 expression and activity.…”