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ISGylation在小鼠结核分枝杆菌感染过程中的影响。

The impact of ISGylation during Mycobacterium tuberculosis infection in mice.

作者信息

Kimmey Jacqueline M, Campbell Jessica A, Weiss Leslie A, Monte Kristen J, Lenschow Deborah J, Stallings Christina L

机构信息

Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.

Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

出版信息

Microbes Infect. 2017 Apr-May;19(4-5):249-258. doi: 10.1016/j.micinf.2016.12.006. Epub 2017 Jan 10.

Abstract

Mycobacterium tuberculosis infection results in 1.5 million deaths annually. Type I interferon (IFN) signaling through its receptor IFNAR correlates with increased severity of disease, although how this increases susceptibility to M. tuberculosis remains uncertain. ISG15 is one of the most highly induced interferon stimulated genes (ISGs) during M. tuberculosis infection. ISG15 functions by conjugation to target proteins (ISGylation), by noncovalent association with intracellular proteins, and by release from the cell. Recent studies indicated that ISG15 can function via conjugation-independent mechanisms to suppress the type I IFN response. These data raised the question of whether ISG15 may have diverse and sometimes opposing functions during M. tuberculosis infection. To address this, we analyzed ISGylation during M. tuberculosis infection and show that ISGylated proteins accumulate following infection in an IFNAR-dependent manner. Type I IFN and ISG15 both play transient roles in promoting bacterial replication. However, as the disease progresses, ISGylation deviates from the overall effect of type I IFN and, ultimately, mice deficient in ISGylation are significantly more susceptible than IFNAR mice. Our data demonstrate that ISGs can both protect against and promote disease and are the first to report a role for ISGylation during M. tuberculosis infection.

摘要

结核分枝杆菌感染每年导致150万人死亡。I型干扰素(IFN)通过其受体IFNAR发出信号,这与疾病严重程度增加相关,尽管其如何增加对结核分枝杆菌的易感性仍不确定。ISG15是结核分枝杆菌感染期间诱导程度最高的干扰素刺激基因(ISG)之一。ISG15通过与靶蛋白结合(ISGylation)、与细胞内蛋白非共价结合以及从细胞中释放来发挥作用。最近的研究表明,ISG15可以通过不依赖结合的机制发挥作用,以抑制I型干扰素反应。这些数据提出了一个问题,即ISG15在结核分枝杆菌感染期间是否可能具有多种、有时甚至是相反的功能。为了解决这个问题,我们分析了结核分枝杆菌感染期间的ISGylation,结果表明,感染后ISGylated蛋白以依赖IFNAR的方式积累。I型干扰素和ISG15在促进细菌复制方面都发挥着短暂的作用。然而,随着疾病的进展,ISGylation偏离了I型干扰素的总体作用,最终,缺乏ISGylation的小鼠比IFNAR小鼠更易感染。我们的数据表明,ISG既能预防疾病,也能促进疾病,并且首次报道了ISGylation在结核分枝杆菌感染中的作用。

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