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

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...

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Published inThe EMBO journal Vol. 40; no. 22; pp. 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 Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 15.11.2021
Springer Nature B.V
John Wiley and Sons Inc
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
Liver cancer
Membrane Proteins - genetics
Membrane Proteins - metabolism
Metabolism
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
tumor growth
total cholesterol levels
PKM2
TMEM33
SCAP degradation
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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. 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.
AbstractList 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.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.
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.
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. Transmembrane protein TMEM33 is a novel target of ER‐localised PKM2 and regulator of cholesterol metabolism.
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. Transmembrane protein TMEM33 is a novel target of ER‐localised PKM2 and regulator of cholesterol metabolism.
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.
Author Gao, Ang
Ma, Min
Xu, Wei
Li, Lingjun
Ma, Gui
Donahue, Kristine
Liu, Fabao
Jia, Chenxi
Zhang, Shengjie
Ma, Fengfei
Wang, Yidan
Liu, Peng
Ong, Irene M
Keles, Sunduz
AuthorAffiliation 6 Department of Chemistry University of Wisconsin‐Madison Madison WI USA
5 Department of Statistics University of Wisconsin‐Madison Madison WI USA
2 School of Pharmacy University of Wisconsin‐Madison Madison WI USA
4 UW Carbone Cancer Center School of Medicine and Public Health University of Wisconsin‐Madison Madison WI USA
3 Department of Biostatistics and Medical Informatics University of Wisconsin‐Madison Madison WI USA
7 Present address: Protein Sciences, Discovery Biologics Merck & Co., Inc. South San Francisco CA USA
8 Present address: State Key Laboratory of Proteomics National Center for Protein Sciences‐Beijing Beijing Proteome Research Center Beijing Institute of Radiation Medicine Beijing China
1 McArdle Laboratory for Cancer Research University of Wisconsin‐Madison Madison WI USA
AuthorAffiliation_xml – name: 2 School of Pharmacy University of Wisconsin‐Madison Madison WI USA
– name: 3 Department of Biostatistics and Medical Informatics University of Wisconsin‐Madison Madison WI USA
– name: 6 Department of Chemistry University of Wisconsin‐Madison Madison WI USA
– name: 7 Present address: Protein Sciences, Discovery Biologics Merck & Co., Inc. South San Francisco CA USA
– name: 5 Department of Statistics University of Wisconsin‐Madison Madison WI USA
– name: 8 Present address: State Key Laboratory of Proteomics National Center for Protein Sciences‐Beijing Beijing Proteome Research Center Beijing Institute of Radiation Medicine Beijing China
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– name: 1 McArdle Laboratory for Cancer Research University of Wisconsin‐Madison Madison WI USA
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  organization: McArdle Laboratory for Cancer Research, University of Wisconsin‐Madison
BackLink https://www.ncbi.nlm.nih.gov/pubmed/34487377$$D View this record in MEDLINE/PubMed
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Fri Jul 25 19:24:38 EDT 2025
Mon Jul 21 06:02:25 EDT 2025
Thu Apr 24 23:07:48 EDT 2025
Tue Jul 01 01:47:23 EDT 2025
Wed Jan 22 16:26:56 EST 2025
Fri Feb 21 02:37:33 EST 2025
IsDoiOpenAccess false
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Issue 22
Keywords tumor growth
total cholesterol levels
PKM2
TMEM33
SCAP degradation
Language English
License 2021 The Authors.
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MergedId FETCHMERGED-LOGICAL-c5855-b192f7c08894d225a050255bdb7f377e0d0064d8da185e2b70ba17af9777f75f3
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A Khateb & ZA Ronai
November 2021
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content type line 14
content type line 23
See also: A Khateb & ZA Ronai (November 2021)
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Snippet The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer cells to regulate anabolic metabolism. Although PKM2 was recently reported to...
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pubmed
crossref
wiley
springer
SourceType Open Access Repository
Aggregation Database
Index Database
Enrichment Source
Publisher
StartPage e108065
SubjectTerms 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
Liver cancer
Membrane Proteins - genetics
Membrane Proteins - metabolism
Metabolism
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
Title PKM2‐TMEM33 axis regulates lipid homeostasis in cancer cells by controlling SCAP stability
URI https://link.springer.com/article/10.15252/embj.2021108065
https://onlinelibrary.wiley.com/doi/abs/10.15252%2Fembj.2021108065
https://www.ncbi.nlm.nih.gov/pubmed/34487377
https://www.proquest.com/docview/2597415034
https://www.proquest.com/docview/2569616850
https://pubmed.ncbi.nlm.nih.gov/PMC8591543
Volume 40
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