The impact of ISGylation during Mycobacterium tuberculosis infection in mice.
The impact of ISGylation during Mycobacterium tuberculosis infection in mice.
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DOI：
10.1016/j.micinf.2016.12.006
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发表时间：
2017-04
影响因子：
5.8
通讯作者：
Stallings CL
中科院分区：
文献类型：
--
作者：
Kimmey JM;Campbell JA;Weiss LA;Monte KJ;Lenschow DJ;Stallings CL
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信号传导与疾病严重程度的增加相关，尽管这如何增加对M的易感性。结核病仍然不确定。ISG15是M.肺结核感染。ISG15通过与靶蛋白偶联（ISGylation）、与细胞内蛋白非共价结合以及从细胞中释放而发挥功能。最近的研究表明，ISG15可以通过缀合非依赖性机制来抑制I型IFN应答。这些数据提出了一个问题，即ISG15在M.肺结核感染。为了解决这个问题，我们分析了M.结核病感染，并显示ISG化蛋白质以IFNAR依赖性方式在感染后积累。I型IFN和ISG15都在促进细菌复制中起瞬时作用。然而，随着疾病的进展，ISG化偏离I型IFN的总体效果，并且最终，ISG化缺陷的小鼠比IFNAR小鼠显著更易感。我们的数据表明，ISGs可以保护和促进疾病，并且是第一个报告ISGylation在M。肺结核感染。
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.