Targeting of chromatin readers: a novel strategy used by the Shigella flexneri virulence effector OspF to reprogram transcription

Abstract

Shigella flexneri, a gram-negative bacterium responsible of bacillary dysentery, uses multiple strategies to overcome host immune defense. We have decrypted how this bacterium manipulates host-cell chromatin binders to take control of immune gene expression. We found that OspF, an injected virulence factor previously identified as a repressor of immune gene expression, targets the chromatin reader HP1γ. Heterochromatin Protein 1 family members specifically recognize and bind histone H3 methylated at Lys 9. Although initially identified as chromatin-associated transcriptional silencers in heterochromatin, their location in euchromatin indicates an active role in gene expression. Notably, HP1γ phosphorylation at Serine 83 defines a subpopulation exclusively located to euchromatin, targeted to the site of transcriptional elongation. We showed that OspF directly interacts with HP1γ, and causes HP1 dephosphorylation, suggesting a model in which this virulence effector "uses" HP1 proteins as beacons to target and repress immune gene expression (Harouz, et al. EMBO J (2014)). OspF alters HP1γ phosphorylation mainly by inactivating the Erk-activated kinase MSK1, spotlighting it as a new HP1 kinase. In vivo, infectious stresses trigger HP1γ phosphorylation in the colon, principally in the lamina propria and the intestinal crypts. Several lines of evidence suggest that HP1 proteins are modified as extensively as histones, and decrypting the impact of these HP1 post-translational modifications on their transcriptional activities in vivo will be the next challenges to be taken up.

Keywords: Heterochromatin protein 1; OspF; Shigella; epigenetic; immune gene.

Figure 1. FIGURE 1: The T3SS virulence effector OspF targets HP1γ and highlights the MSK1/HP1γ chromatin interplay at immune genes.

Under physiological conditions (A) MAPK signaling leads to HP1γ and histone 3 serine 10 (H3S10) phosphorylation, allowing fine tuning of immune gene expression. Upon infection (B) Shigella injects the virulence factor OspF into the host cell. OspF translocates to the nucleus and both, binds to HP1γ as well as inactivates MAPK irreversibly by altering the phosphorylation site. Dephosphorylated HP1γ and H3S10 lead to repressed transcription of immune genes, and thus drive Shigella infection.