法国科学家最近研究发现，一种重要的细菌李斯特菌感染细胞的新模式。这种细菌可以分泌一种物质，这种物质可以把宿主细胞内SIRT2转移到细胞核内，然后导致一种脱乙酰化酶，导致宿主细胞基因表达受到抑制。具体过程是细菌释放一种蛋白InlB和宿主细胞膜上一种受体Met结合，然后启动PI3K/AKT（胰岛素也是利用这个通路，那么这个细菌蛋白也许是一种类似胰岛素的东西）信号传导，最后感染的细胞内SIRT2蛋白活性被激活，后者进入细胞核，通过对组蛋白histone H3 on lysine 18 (H3K18)的脱乙酰化，最终使宿主细胞基因表达受到抑制。这是细菌感染细胞的一种新模式，可望使科学家开发出治疗细菌感染的新方法。当然也许是通过学习细菌的工作方式，建立一种治疗疾病的手段。该论文发表在今日《科学》杂志。

李斯特菌（学名：Listeria monocytogenes），又名单核球增多性李斯特菌、李氏菌，是一种兼性厌氧细菌[1]，为李斯特菌症的病原体。

它主要以食物为传染媒介，是最致命的食源性病原体之一，造成二至三成的感染者死亡[2]。李斯特菌在美国每年约引起2500份病例、500人死亡，其中李斯特菌症是导致死亡的主要病因，其致死率甚至高过沙门氏菌及肉毒杆菌[3]。

李斯特菌是革兰氏阳性菌，属厚壁菌门，取名自约瑟夫·李斯特。它在30°C以下的环境中具能动性，但通常不耐超过37°C的高温；而除了以鞭毛运动之外，李斯特菌也能透过肌动蛋白丝状物的爆炸性聚合（简称爆聚），藉真核细胞进行活动，即所谓的“彗尾”（comet tails）或“肌动蛋白火箭”（actin rockets）[4]。

研究显示，约一成的人类消化系统内滋长有李斯特菌[5]。然而，兽医才是碰上以李斯特菌为祸首之临床病例的大宗，而病例中又以反刍动物感染脑膜脑炎的情况最为显见。

李斯特菌具有相当的致病性，能经由妇女的阴部感染腹中胎儿、引发脑膜炎，因此怀孕妇女通常不建议食用未经低温杀菌的软质奶酪，如：布利奶酪、卡门培尔奶酪、菲达奶酪、克索布兰可奶酪等[6][7]。

近期，李斯特菌则在疾病生物科技领域被用作模式生物来解释相关学说。

A Role for SIRT2-Dependent Histone H3K18 Deacetylationin Bacterial Infection

Introduction

Posttranslational modification of histones is awell-documented mechanism by which the chromatin structure is modulated to regulategene expression. Increasing evidence is revealing the strong impact ofbacterial pathogens on host chromatin. However, our knowledge of the mechanismsunderlying pathogen-induced chromatin changes and the impact of histonemodifications and chromatin modifiers on infection is still in its infancy.

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Mechanism and consequence of SIRT2 activation by L.monocytogenes.Listeriainduces SIRT2 relocalization from cytoplasm to chromatin, where SIRT2deacetylates H3K18. The consequences of this cascade are control of hosttranscription, as illustrated by representative genes regulated by SIRT2, andcontrol of infection, as assessed by staining cells for the secreted bacterialfactor InlC (red), which is overexpressed in the cytosol, and host actin, whichis polymerized into comet tails by bacteria (green). Error bars indicate SEM;**P < 0.001. Ac, acetyl; deAc, deacetylase.

Methods

We used the model bacterium Listeriamonocytogenesand analyzed the mechanisms underlying a specific histone modification, deacetylationof histone H3 on lysine 18 (H3K18). Through immunoblotting, mass spectrometry,and chromatin immunoprecipitation, we studied how infection affected thismodification, both in vitro and in vivo. We used a combination of chemicalinhibitors, small interfering RNA (siRNA), and knockout mice to discover thekey role of the host histone deacetylase sirtuin 2 (SIRT2) and determine itseffect on infection. We performed microarray analysis to identify how infectionand SIRT2 modulated host transcription.

Results

L. monocytogenes induces deacetylation of H3K18. This modification ismediated by the host deacetylase SIRT2. Upon infection, SIRT2 translocates fromthe cytosol to the chromatin of the host at the transcription start sites of asubset of genes that are repressed. We find that this process is dependent onactivation, by the bacterial protein InlB, of the cell surface receptor Met anddownstream phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Finally,infecting cells in which SIRT2 activity was blocked (by pharmacological agents,treatment with siRNA, or the use of SIRT2^–/– mice) resulted in asignificant impairment of bacterial infection, showing that activity of SIRT2is necessary for infection, both in vitro and in vivo.

Discussion

Our study identifies a stimulus, infection by L.monocytogenes, that leads to nuclear localization of SIRT2, a deacetylasepreviously shown to be mainly cytoplasmic. In fact, only upon infection andSIRT2 translocation from the cytoplasm to the chromatin does this deacetylasehave a role in transcriptional repression. This mechanism of host subversioncould be common to other invasive pathogens that induce deacetylation ofhistones, and it defines a target for potential therapeutic treatment.