Research Article

A Role for SIRT2-Dependent Histone H3K18 Deacetylation in Bacterial Infection

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Science  02 Aug 2013:
Vol. 341, Issue 6145, 1238858
DOI: 10.1126/science.1238858

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Structured Abstract


Posttranslational modification of histones is a well-documented mechanism by which the chromatin structure is modulated to regulate gene expression. Increasing evidence is revealing the strong impact of bacterial pathogens on host chromatin. However, our knowledge of the mechanisms underlying pathogen-induced chromatin changes and the impact of histone modifications and chromatin modifiers on infection is still in its infancy.

Embedded Image

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


We used the model bacterium Listeria monocytogenes and analyzed the mechanisms underlying a specific histone modification, deacetylation of histone H3 on lysine 18 (H3K18). Through immunoblotting, mass spectrometry, and chromatin immunoprecipitation, we studied how infection affected this modification, both in vitro and in vivo. We used a combination of chemical inhibitors, small interfering RNA (siRNA), and knockout mice to discover the key role of the host histone deacetylase sirtuin 2 (SIRT2) and determine its effect on infection. We performed microarray analysis to identify how infection and SIRT2 modulated host transcription.


L. monocytogenes induces deacetylation of H3K18. This modification is mediated by the host deacetylase SIRT2. Upon infection, SIRT2 translocates from the cytosol to the chromatin of the host at the transcription start sites of a subset of genes that are repressed. We find that this process is dependent on activation, by the bacterial protein InlB, of the cell surface receptor Met and downstream 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 a significant impairment of bacterial infection, showing that activity of SIRT2 is necessary for infection, both in vitro and in vivo.


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

Bacterial Subversion Tactics

Intracellular bacterial pathogens such as Listeria monocytogenes can change host cell transcription programs to promote infection. Eskandarian et al. (1238858) found that during infection, the Listeria effector protein InlB promoted the movement of a host protein deacetylase, SIRT2, from its normal location in the cytosol to the nucleus. In the nucleus, SIRT2 helped to repress a number of host cell genes by deacetylating one of their associated histones. In mice, reduced levels of SIRT2 impaired bacterial infection.


Pathogens dramatically affect host cell transcription programs for their own profit during infection, but in most cases, the underlying mechanisms remain elusive. We found that during infection with the bacterium Listeria monocytogenes, the host deacetylase sirtuin 2 (SIRT2) translocates to the nucleus, in a manner dependent on the bacterial factor InlB. SIRT2 associates with the transcription start site of a subset of genes repressed during infection and deacetylates histone H3 on lysine 18 (H3K18). Infecting cells in which SIRT2 activity was blocked or using SIRT2−/− mice resulted in a significant impairment of bacterial infection. Thus, SIRT2-mediated H3K18 deacetylation plays a critical role during infection, which reveals an epigenetic mechanism imposed by a pathogenic bacterium to reprogram its host.

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