果糖-1,6-二磷酸酶 1 介导的去磷酸化作用可抑制 TERT 进入细胞核。

IF 20.1 1区 医学 Q1 ONCOLOGY
Pengbo Yao, Gaoxiang Zhao, Min Li, Wensheng Qiu, Zhimin Lu
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This translocation requires AKT-mediated TERT S227 phosphorylation and subsequent binding of the nuclear localization signal (NLS) of TERT to importin α [<span>2</span>]. However, whether cancer cells and normal cells differentially regulate TERT phosphorylation and telomere functions remain largely unknown.</p><p>We recently demonstrated that fructose 1,6-bisphosphatase 1 (FBP1), the rate-limiting gluconeogenic enzyme that converts fructose 1,6-bisphosphate (F-1,6-BP) to fructose 6-phosphate (F-6-P), acts as a protein phosphatase and dephosphorylates TERT [<span>3</span>]. Through analyses of FBP1 immunoprecipitants from hepatocellular carcinoma (HCC) Huh7 cells by mass spectrometry, TERT was identified as an FBP1-associated protein, and this interaction was primarily in the cytosol. An in vitro glutathione S-transferase (GST) pulldown assay showed that FBP1 directly bound to TERT, and truncation and mutagenesis analyses identified that asparagine (N)273 of FBP1 is a key residue involving in binding to TERT. Importantly, a protein dephosphorylation assay showed that wild-type (WT) FBP1, but not FBP1 N273A mutant, dephosphorylated AKT1-phosphorylated TERT at S227. Notably, FBP1 G260R, a metabolically inactive mutant defected in its binding to F-1,6-BP, was still able to dephosphorylate TERT, indicating that FBP1 dephosphorylates TERT independent of its gluconeogenic activity.</p><p>The catalytic domain of conventional protein phosphatases contains a conserved and reduced cysteine (C), which is critical for the dephosphorylation of protein substrates. Molecular docking analyses showed that the phosphorylated S227 residue of TERT was in close proximity to C129 of FBP1 [<span>3</span>]. In addition, during the process of the dephosphorylation, FBP1 formed a covalent phospho-C129 intermediate. FBP1 C129S mutant, which had comparable metabolic activity to its WT counterpart, lost its ability to dephosphorylate TERT pS227 both in vitro and in vivo. Structural analyses revealed that a binding pocket was formed by FBP1 C129, R244 and D128, which interact with the phosphate group of pS227 of TERT. Notably, mutations of FBP1 R244 or D128 also decreased TERT pS227 dephosphorylation by FBP1.</p><p>As expected, FBP1 depletion enhanced the nuclear translocation of TERT and telomerase activity, leading to increased telomere lengths in normal human renal cells [<span>3</span>]. In contrast, in clear cell renal cell carcinoma (ccRCC) cells with deficiency in FBP1 expression, ectopic expression of WT FBP1, but not FBP1 C129S or FBP1 N273A reduced nuclear TERT levels and activity of telomerase, resulting in decreased telomere lengths and increased cell senescence. In addition, the expression of these proteins did not alter the alternative lengthening of telomere (ALT) pathway. Mouse studies showed that WT FBP1 expression substantially promoted anaphase bridge formation, a feature of dysfunctional telomere, enhanced cell senescence in tumors, and inhibited tumor growth that accompanied with decreased levels of TERT S227 phosphorylation. In contrast, the expression of FBP1 C129S and FBP1 N273A, to a large extent, failed to inhibit tumor growth and tumor cell senescence (Figure 1). In addition, FBP1 expression levels and TERT pS227 levels were inversely correlated with each other in ccRCC and HCC specimens and poor prognosis of the patients. 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Glycolytic enzymes, including hexokinase, phosphoglycerate kinase 1, pyruvate kinase M2, as well as other metabolic enzymes such as ketohexokinase isoform A, phosphoenolpyruvate carboxykinase 1, choline kinase α2, and creatine kinase B, exhibit protein kinase activity. They phosphorylate diverse protein substrates critical for various cellular activities [<span>6, 7</span>]. The finding of FBP1's protein phosphatase activity in dephosphorylation of histone H3 and TERT reshapes the understanding of the moonlighting functions of metabolic enzymes, involving both phosphorylation and dephosphorylation of proteins [<span>8</span>]. The deficiency in expression of gluconeogenic enzyme FBP1 in tumor cells promotes cell proliferation not only by facilitating the Warburg effect but also through the loss of its protein phosphatase activity. 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引用次数: 0

摘要

糖酵解酶,包括己糖激酶、磷酸甘油酸激酶 1、丙酮酸激酶 M2,以及其他代谢酶,如酮己糖激酶异构体 A、磷酸烯醇丙酮酸羧激酶 1、胆碱激酶 α2、肌酸激酶 B,都具有蛋白激酶活性。它们将对各种细胞活动至关重要的多种蛋白质底物磷酸化 [6,7]。FBP1 在组蛋白 H3 和 TERT 的去磷酸化过程中具有蛋白磷酸酶活性,这一发现重塑了人们对代谢酶月光功能的认识,其中涉及蛋白的磷酸化和去磷酸化[8]。肿瘤细胞中葡萄糖生成酶 FBP1 表达不足,不仅会促进沃伯格效应,而且会丧失其蛋白磷酸酶活性,从而促进细胞增殖。研究表明,FBP1 能够使组蛋白 H3 的 T11 和 B 细胞中卡巴轻多肽基因增强子抑制因子α(IκBα)去磷酸化,从而分别抑制组蛋白 H3T11 磷酸化依赖性基因转录和核因子κB(NF-κB)的活性[9, 10]。FBP1 在 TERT 的去磷酸化和端粒功能抑制过程中起着关键作用,这一发现强调了 FBP1 在调节细胞衰老和永生中的未知作用。概念验证研究表明,LNP-FBP1 mRNA能有效抑制肿瘤生长,为癌症治疗提供了一种有吸引力的策略。陆志敏博士、邱文胜、姚鹏博、赵高翔和李敏撰写了手稿。陆志敏博士拥有 Signalway 生物技术公司(美国德克萨斯州皮尔兰市)的股份。陆志敏博士在该公司的股份与该公司被选为试剂供应商无关。本研究中人体样本的使用获得了浙江大学医学院附属第一医院研究伦理委员会的批准,并符合所有相关伦理法规。所有组织样本的采集均符合知情同意政策。动物实验按照浙江大学医学院附属第一医院机构审查委员会批准的实验动物护理和使用指南进行。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Abrogation of nuclear entry of TERT by fructose 1,6-bisphosphatase 1-mediated dephosphorylation

Abrogation of nuclear entry of TERT by fructose 1,6-bisphosphatase 1-mediated dephosphorylation

Telomeres maintain chromosome integrity. Loss of telomere function, which is attributed to progressively shortened telomeres in each round of DNA replication, induces end-to-end fusion of chromosomes, anaphase bridges with subsequent chromosome breakage, and eventually leads to senescence and apoptosis in normal cells [1]. In cancer cells, highly activated telomerase synthesizes telomere repeats to promote telomere elongation. For assembling catalytically active telomerase, cytoplasmic telomerase reverse transcriptase (TERT), which is the catalytic protein subunit of telomerase, needs to translocate into the nucleus. This translocation requires AKT-mediated TERT S227 phosphorylation and subsequent binding of the nuclear localization signal (NLS) of TERT to importin α [2]. However, whether cancer cells and normal cells differentially regulate TERT phosphorylation and telomere functions remain largely unknown.

We recently demonstrated that fructose 1,6-bisphosphatase 1 (FBP1), the rate-limiting gluconeogenic enzyme that converts fructose 1,6-bisphosphate (F-1,6-BP) to fructose 6-phosphate (F-6-P), acts as a protein phosphatase and dephosphorylates TERT [3]. Through analyses of FBP1 immunoprecipitants from hepatocellular carcinoma (HCC) Huh7 cells by mass spectrometry, TERT was identified as an FBP1-associated protein, and this interaction was primarily in the cytosol. An in vitro glutathione S-transferase (GST) pulldown assay showed that FBP1 directly bound to TERT, and truncation and mutagenesis analyses identified that asparagine (N)273 of FBP1 is a key residue involving in binding to TERT. Importantly, a protein dephosphorylation assay showed that wild-type (WT) FBP1, but not FBP1 N273A mutant, dephosphorylated AKT1-phosphorylated TERT at S227. Notably, FBP1 G260R, a metabolically inactive mutant defected in its binding to F-1,6-BP, was still able to dephosphorylate TERT, indicating that FBP1 dephosphorylates TERT independent of its gluconeogenic activity.

The catalytic domain of conventional protein phosphatases contains a conserved and reduced cysteine (C), which is critical for the dephosphorylation of protein substrates. Molecular docking analyses showed that the phosphorylated S227 residue of TERT was in close proximity to C129 of FBP1 [3]. In addition, during the process of the dephosphorylation, FBP1 formed a covalent phospho-C129 intermediate. FBP1 C129S mutant, which had comparable metabolic activity to its WT counterpart, lost its ability to dephosphorylate TERT pS227 both in vitro and in vivo. Structural analyses revealed that a binding pocket was formed by FBP1 C129, R244 and D128, which interact with the phosphate group of pS227 of TERT. Notably, mutations of FBP1 R244 or D128 also decreased TERT pS227 dephosphorylation by FBP1.

As expected, FBP1 depletion enhanced the nuclear translocation of TERT and telomerase activity, leading to increased telomere lengths in normal human renal cells [3]. In contrast, in clear cell renal cell carcinoma (ccRCC) cells with deficiency in FBP1 expression, ectopic expression of WT FBP1, but not FBP1 C129S or FBP1 N273A reduced nuclear TERT levels and activity of telomerase, resulting in decreased telomere lengths and increased cell senescence. In addition, the expression of these proteins did not alter the alternative lengthening of telomere (ALT) pathway. Mouse studies showed that WT FBP1 expression substantially promoted anaphase bridge formation, a feature of dysfunctional telomere, enhanced cell senescence in tumors, and inhibited tumor growth that accompanied with decreased levels of TERT S227 phosphorylation. In contrast, the expression of FBP1 C129S and FBP1 N273A, to a large extent, failed to inhibit tumor growth and tumor cell senescence (Figure 1). In addition, FBP1 expression levels and TERT pS227 levels were inversely correlated with each other in ccRCC and HCC specimens and poor prognosis of the patients. These results indicate that FBP1 acts as a tumor suppressor and inhibits tumor growth through TERT pS227 dephosphorylation.

To explore the therapeutic potential of employing FBP1's tumor-suppressing function to treat cancer, animal studies were conducted using lipid nanoparticles (LNPs) to deliver FBP1 mRNA [3]. Intravenous delivery of LNP-FBP1 mRNA, which contained an Arg-Gly-Asp (RGD) tripeptide on the surface of LNP for binding to integrin overly expressed in tumor cell membrane, markedly reduced glycolytic flux in the tumor tissues and inhibited tumor growth. Of note, treatment with the LNPs did not elicit obvious adverse effects.

Tumor cell proliferation relies on substantially increased glycolysis regardless of oxygen availability, which is known as the Warburg effect [4]. As a gluconeogenic enzyme, FBP1 inhibited growth of acute myeloid leukemia through anti-Warburg effect [5]. Glycolytic enzymes, including hexokinase, phosphoglycerate kinase 1, pyruvate kinase M2, as well as other metabolic enzymes such as ketohexokinase isoform A, phosphoenolpyruvate carboxykinase 1, choline kinase α2, and creatine kinase B, exhibit protein kinase activity. They phosphorylate diverse protein substrates critical for various cellular activities [6, 7]. The finding of FBP1's protein phosphatase activity in dephosphorylation of histone H3 and TERT reshapes the understanding of the moonlighting functions of metabolic enzymes, involving both phosphorylation and dephosphorylation of proteins [8]. The deficiency in expression of gluconeogenic enzyme FBP1 in tumor cells promotes cell proliferation not only by facilitating the Warburg effect but also through the loss of its protein phosphatase activity. FBP1 has been shown to be able to dephosphorylate histone H3 at T11 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), resulting in suppression of histone H3T11 phosphorylation-dependent gene transcription and nuclear factor κB (NF-κB) activity, respectively [9, 10]. The finding that FBP1 plays a critical role in the dephosphorylation of TERT and the inhibition of telomere function underscores its previously unknown role in regulating cell senescence and immortality. The proof-of-concept studies showing that LNP-FBP1 mRNA effectively attenuated tumor growth provide an attractive strategy for cancer treatment.

Zhimin Lu and Wensheng Qiu conceptualized the writing. Zhimin Lu, Wensheng Qiu, Pengbo Yao, Gaoxiang Zhao, and Min Li wrote the manuscript.

Dr. Zhimin Lu owns shares in Signalway Biotechnology (Pearland, TX, USA). Dr. Lu's interest in this company had no bearing on its being chosen to supply the reagents. The remaining authors declare no competing interests.

The use of human samples in this study was approved by the Research Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine and complied with all relevant ethical regulations. All tissue samples were collected in compliance with the informed consent policy. Animal experiments were performed according to the institutional guidelines for the care and use of laboratory animals approved by the Institutional Review Board at The First Affiliated Hospital, Zhejiang University School of Medicine.

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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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