Legionella pneumophila Effector RomA Uniquely Modifies Host Chromatin to Repress Gene Expression and Promote Intracellular Bacterial Replication

Monica Rolando, Serena Sanulli, Christophe Rusniok, Laura Gomez-Valero, Clement Bertholet, Tobias Sahr, Raphael Margueron, and Carmen Buchrieser. Cell Host Microbe (2013) 13: 395–405

Speaker: Wei-Ting Li (李瑋庭)               Time: 13:00~14:00, Nov. 27, 2013

Commentator: Dr. Pei-Jane Tsai (蔡佩珍 老師)  Place: Room 601

Abstract:

Legionella pneumophila, a Gram-negative bacterium that can invade and replicate intracellularly within both environmental protozoa and mammalian alveolar macrophages, causes severe pneumonia called Legionnaires’ disease in humans. In recent years, many studies have been conducted to identify the bacterial factors that promote intracellular infection (1). In this study, the authors identified a Dot/Icm type IV system-secreted effector of L. pneumophila, RomA. This protein contains an eukaryotic-like SET domain that functions as a potent histone methyltransferase. By mass spectrometry they showed that RomA uniquely trimethylated K14 of histone H3, a histone marker that had never been observed as methylated in mammals. RomA was predicted to contain a nuclear localization signal at its N-terminus. The results of in vivo experiments revealed that this protein indeed targeted the host cell nucleus and triggered H3K14 trimethylation(H3K14_me3). As a result, normal acetylation of this residue (H3K14_ac), which is correlated with active transcription (2), was prevented. This modification induced by RomA led to repression of host gene expression. A mutant with mutations in the SET domain of RomA resulted in more H3K14_ac than H3K14_{me3 in the host cell, indicating that this domain is essential for the enzymatic activity. The}genes repressed by H3K14_me3 were identified by ChIP-seq, and the results indicated that a number of them were related to the innate immune response. Finally, the authors demonstrated that the replication of RomA-deficient L. pneumophila (Δlpp1683) mutant within host cells was significantly reduced as compared to the wild-type strain, but this defect was restored by trans-complemented lpp1683 gene. In conclusion, RomA of L. pneumophila is secreted into the host cell upon infection, and then delivered to the nucleus where histone 3 is trimethylated to repress host gene expression and, consequently, promote efficient intracellular replication.

References:

1.       Hubber, A., and Roy, C.R. Modulation of host cell function by Legionella pneumophila type IV effectors. Annu. Rev. Cell Dev. Biol (2010) 26: 261–283.

2.       Karmodiya, K., Krebs, A.R., Oulad-Abdelghani, M., Kimura, H., and Tora, L. H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells. BMC Genomics, (2012) 13: 424.