Unpaired cysteine insertions favor transmembrane dimerization and induce ligand-independent constitutive cytokine receptor signaling

IF 2.9 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lynn Affrica Felicitas Baumgärtner, Julia Ettich, Helene Balles, Dorothee Johanna Lapp, Sofie Mossner, Christin Bassenge, Meryem Ouzin, Helmut Hanenberg, Jürgen Scheller, Doreen Manuela Floss
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引用次数: 0

Abstract

Naturally occurring gain-of-function (GOF) mutants have been identified in patients for a variety of cytokine receptors. Although this constitutive activation of cytokine receptors is strongly associated with malignant disorders, ligand-independent receptor activation is also a useful tool in synthetic biology e.g. to improve adoptive cellular therapies with genetically modified T-cells. Balanced Interleukin (IL-)7 signaling via a heterodimer of IL-7 receptor (IL-7Rα) and the common γ-chain (γc) controls T- and B-cell development and expansion, whereas uncontrolled IL-7 signaling can drive acute lymphoid leukemia (ALL) development. The ALL-driver mutation PPCL in the transmembrane domain of IL-7Rα is a mutational insertion of the four amino acids proline-proline-cysteine-leucine and leads to ligand-independent receptor dimerization and constitutive activation. We showed here in the cytokine-dependent pre-B-cell line Ba/F3 that the PPCL-insertion in a synthetic version of the IL-7Rα induced γc-independent STAT5 and ERK phosphorylation and also proliferation of the cells and that booster-stimulation by arteficial ligands additionally generated non-canonical STAT3 phosphorylation via the synthetic IL-7Rα-PPCL-receptors. Transfer of the IL-7Rα transmembrane domain with the PPCL insertion into natural and synthetic cytokine receptor chains of the IL-6, IL-12 and Interferon families also resulted in constitutive receptor signaling. In conclusion, our data suggested that the insertion of the mutated PPCL IL-7Rα transmembrane domain is an universal approach to generate ligand-independent, constitutively active cytokine receptors.
非配对半胱氨酸插入有利于跨膜二聚化并诱导配体依赖性组成型细胞因子受体信号转导
在患者体内发现了多种细胞因子受体的天然功能增益(GOF)突变体。虽然细胞因子受体的这种组成性激活与恶性疾病密切相关,但不依赖配体的受体激活也是合成生物学中的一种有用工具,例如,可用于改进使用转基因 T 细胞的收养性细胞疗法。白细胞介素(IL-)7 信号通过 IL-7 受体(IL-7Rα)和常见的 γ 链(γc)的异二聚体平衡地控制着 T 细胞和 B 细胞的发育和扩增,而不受控制的 IL-7 信号则会导致急性淋巴白血病(ALL)的发生。IL-7Rα跨膜结构域的ALL驱动突变PPCL是脯氨酸-脯氨酸-半胱氨酸-亮氨酸四个氨基酸的突变插入,导致配体依赖性受体二聚化和组成性激活。我们在细胞因子依赖性前 B 细胞系 Ba/F3 中发现,在 IL-7Rα 的合成版本中插入 PPCL 可诱导 γc 依赖性 STAT5 和 ERK 磷酸化,并使细胞增殖,而且通过合成的 IL-7Rα-PPCL 受体,表面配体的增效刺激还可产生非规范 STAT3 磷酸化。将带有 PPCL 插入物的 IL-7Rα 跨膜结构域转移到 IL-6、IL-12 和干扰素家族的天然和合成细胞因子受体链中也会导致组成型受体信号转导。总之,我们的数据表明,插入突变的 PPCL IL-7Rα 跨膜结构域是产生配体依赖性、组成型活性细胞因子受体的通用方法。
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来源期刊
Biological Chemistry
Biological Chemistry 生物-生化与分子生物学
CiteScore
7.20
自引率
0.00%
发文量
63
审稿时长
4-8 weeks
期刊介绍: Biological Chemistry keeps you up-to-date with all new developments in the molecular life sciences. In addition to original research reports, authoritative reviews written by leading researchers in the field keep you informed about the latest advances in the molecular life sciences. Rapid, yet rigorous reviewing ensures fast access to recent research results of exceptional significance in the biological sciences. Papers are published in a "Just Accepted" format within approx.72 hours of acceptance.
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