Abstract
For many intracellular bacterial pathogens manipulating host cell survival is essential for maintaining their replicative niche, and is a common strategy used to promote infection. The bacterial pathogen Listeria monocytogenes is well known to hijack host machinery for its own benefit, such as targeting the host histone H3 for modification by SIRT2. However, by what means this modification benefits infection, as well as the molecular players involved, were unknown. Here we show that SIRT2 activity supports Listeria intracellular survival by maintaining genome integrity and host cell viability. This protective effect is dependent on H3K18 deacetylation, which safeguards the host genome by counteracting infection-induced DNA damage. Mechanistically, infection causes SIRT2 to interact with the nucleic acid binding protein TDP-43 and localise to genomic R-loops, where H3K18 deacetylation occurs. This work highlights novel functions of TDP-43 and R-loops during bacterial infection and identifies the mechanism through which L. monocytogenes co-opts SIRT2 to allow efficient infection.
Highlights
Intracellular parasitism requires a delicate balance between pathogen growth and the maintenance of the intracellular niche as premature death of the host cell would lead to inefficient infection
We show that an interaction with the DNA/RNA binding protein TDP-43 is essential for Sirtuin 2 (SIRT2) enrichment at the transcription start site (TSS) of SIRT2-regulated genes and H3K18 deacetylation during infection
Consistent with our previous interactome analysis these data show that a basal interaction between SIRT2 and TDP-43 occurs in the nuclei of uninfected cells, and we show that this interaction is significantly enhanced in response to L. monocytogenes infection
Summary
Intracellular parasitism requires a delicate balance between pathogen growth and the maintenance of the intracellular niche as premature death of the host cell would lead to inefficient infection. The Sirtuin family (SIRT1-7) of NAD+-dependent deacetylases are vital protective factors against numerous cellular stresses, and play key roles in many biological processes that maintain cellular homeostasis, including cell cycle, metabolism and DNA repair [1,2], their roles during infection have not been well characterised. Our previous work identified a novel function of Sirtuin 2 (SIRT2) during infection with the bacterial pathogen Listeria monocytogenes which causes SIRT2-nuclear accumulation. Upon infection SIRT2 becomes enriched on chromatin at the transcriptional start sites (TSSs) of certain genes and induces deacetylation of H3K18 independently of the cell cycle [3]. Nuclear import of SIRT2, mediated in part by importin IPO7; and dephosphorylation of SIRT2 at serine 25 to permit chromatin binding, enable H3K18 deacetylation [4,5]. SIRT2 activity at chromatin is essential for efficient L. monocytogenes infection in vitro and in vivo though how bacterial hijacking of SIRT2 promotes infection remains unknown
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