Group A Streptococcal asparagine metabolism regulates bacterial virulence.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-05-01 Epub Date: 2025-04-14 DOI:10.1038/s44319-025-00447-z

Abhinay Sharma, Aparna Anand, Miriam Ravins, Xiaolan Zhang, Nicola Horstmann, Samuel A Shelburne, Kevin S McIver, Emanuel Hanski

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引用次数: 0

Abstract

Group A Streptococcus (GAS) causes various human diseases linked to virulome expression predominantly regulated by the two-component system (TCS), CovR/S. Here, we demonstrate that asparagine (Asn) presence in a minimal chemically defined medium increases virulence gene expression in a CovR-dependent fashion. It also decreases the transcription of asparagine synthetase (AsnA), the ABC transporter responsible for Asn uptake (GlnPQ), and that of the hemolysin toxins responsible for scavenging Asn from the host. Metabolomics data show that Asn availability increases intracellular ADP/ATP ratio, which enhances phosphatase activity in structurally related CovS sensors and is probably responsible for the Asn-mediated decrease in CovR phosphorylation. Mutants deficient in AsnA, GlnPQ, asparaginase, (AsnB) activities are attenuated in a mouse model of human GAS invasive soft tissue infection. The similarity between the mechanisms of Asn-mediated regulation of GAS virulence and tumor growth suggests that, as in cancer, components maintaining Asn homeostasis could be targeted for anti-GAS treatments.

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A组链球菌天冬酰胺代谢调节细菌毒力。

A群链球菌（GAS）引起多种人类疾病，与主要由双组分系统（TCS） CovR/S调控的病毒组表达有关。在这里，我们证明了天冬酰胺（Asn）存在于最小的化学定义的培养基中，以cov依赖的方式增加了毒力基因的表达。它还降低了天冬酰胺合成酶（AsnA）的转录，天冬酰胺合成酶是负责Asn摄取的ABC转运蛋白（GlnPQ），以及负责从宿主清除Asn的溶血素毒素的转录。代谢组学数据显示，Asn的可用性增加了细胞内ADP/ATP比率，从而增强了结构相关的cov传感器中磷酸酶的活性，这可能是Asn介导的CovR磷酸化降低的原因。缺乏AsnA、GlnPQ、天冬酰胺酶（AsnB）活性的突变体在人GAS侵袭性软组织感染的小鼠模型中被减弱。Asn介导的GAS毒力调控和肿瘤生长机制之间的相似性表明，在癌症中，维持Asn稳态的成分可能成为抗GAS治疗的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.