G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-11-19 DOI:10.1172/JCI177342
Ramesh C Nayak, Sana Emberesh, Lisa Trump, Ashley Wellendorf, Abhishek Singh, Brice Korkmaz, Marshall S Horwitz, Kasiani C Myers, Theodosia A Kalfa, Carolyn Lutzko, Jose A Cancelas
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Abstract

Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients including patients with ELANE start codon mutations do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF resistant granulocytic precursor cell death and refractory SCN. ELANE start codon mutated neutrophil precursors express predominantly nuclear N-terminal truncated alternate NE. Unlike G-CSF sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated pro-apoptotic aggrephagy as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE co-localization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight of G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.

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ELANE突变型中性粒细胞减少症的G-CSF抗性取决于含有截短的中性粒细胞弹性蛋白酶聚集体的SERF1。
重度先天性中性粒细胞减少症(SCN)常常与编码中性粒细胞弹性蛋白酶(NE)的基因 ELANE 的显性点突变有关。长期服用粒细胞集落刺激因子(G-CSF)是治疗 ELANE 突变(ELANEmut)SCN 的一线疗法。然而,一些ELANEmut患者,包括ELANE起始密码子突变患者,对G-CSF没有反应。在这里,我们通过基因编辑的同源正常和患者衍生 iPSCs 的定向粒细胞生成,证明了 ELANE 起始密码子突变足以诱导 G-CSF 抗性粒细胞前体细胞死亡和难治性 SCN。ELANE起始密码子突变的中性粒细胞前体细胞主要表达核N末端截短的交替NE。与诱导内质网和未折叠蛋白反应应激的 G-CSF 敏感 ELANE 突变不同,我们发现 ELANE 翻译起始密码子突变会导致 NE 聚集并激活促凋亡的凝集作用,具体表现为 BAG1 表达下调、BAG1/BAG3 比率下降、NE 与 BAG3 共定位以及自噬 LC3B 的定位表达。我们发现,在神经退行性疾病中,SERF1是一种RNA伴侣蛋白,已知会定位在错误折叠的蛋白质聚集体中,它的表达高度上调,并与突变中性粒细胞前体的细胞质NE相互作用。沉默 SERF1 能增强 iPSC 衍生的中性粒细胞前体的存活和分化,恢复它们对 G-CSF 的反应性。这些观察结果提供了对 G-CSF 抗性 ELANEmut SCN 的机理认识,揭示了治疗干预的靶点。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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