Tafazzin regulates neutrophil maturation and inflammatory response.

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-17 DOI:10.1038/s44319-025-00393-w

Przemysław Zakrzewski, Christopher M Rice, Kathryn Fleming, Drinalda Cela, Sarah J Groves, Fernando M Ponce-Garcia, Willem Gibbs, Kiran Roberts, Tobias Pike, Douglas Strathdee, Eve Anderson, Angela H Nobbs, Ashley M Toye, Colin Steward, Borko Amulic

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Abstract

Barth syndrome (BTHS) is a rare genetic disease caused by mutations in the TAFAZZIN gene. It is characterized by neutropenia, cardiomyopathy and skeletal myopathy. Neutropenia in BTHS is associated with life-threatening infections, yet there is little understanding of the molecular and physiological causes of this phenomenon. We combined bone marrow analysis, CRISPR/Cas9 genome editing in hematopoietic stem cells and functional characterization of circulating BTHS patient neutrophils to investigate the role of TAFAZZIN in neutrophils and their progenitors. We demonstrate a partial cell intrinsic differentiation defect, along with a dysregulated neutrophil inflammatory response in BTHS, including elevated degranulation and formation of neutrophil extracellular traps (NETs) in response to calcium flux. Developmental and functional alterations in BTHS neutrophils are underpinned by perturbations in the unfolded protein response (UPR) signaling pathway, suggesting potential therapeutic avenues for targeting BTHS neutropenia.

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他法嗪调节中性粒细胞成熟和炎症反应。

Barth综合征（BTHS）是一种罕见的由TAFAZZIN基因突变引起的遗传病。它的特点是中性粒细胞减少，心肌病和骨骼肌病。BTHS中性粒细胞减少与危及生命的感染有关，但对这种现象的分子和生理原因知之甚少。我们结合骨髓分析、造血干细胞CRISPR/Cas9基因组编辑和循环BTHS患者中性粒细胞的功能表征，研究TAFAZZIN在中性粒细胞及其祖细胞中的作用。我们证明了BTHS的部分细胞内在分化缺陷，以及中性粒细胞炎症反应失调，包括脱颗粒升高和中性粒细胞细胞外陷阱（NETs）的形成，以响应钙通量。未折叠蛋白反应（UPR）信号通路的扰动支持BTHS中性粒细胞的发育和功能改变，提示针对BTHS中性粒细胞减少的潜在治疗途径。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.