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

摘要

Shigella flexneri, a gram-negative bacteriumresponsible of bacillary dysentery, uses multiplestrategies to overcome host immune defense. We havedecrypted how this bacterium manipulates host-cellchromatin binders to take control of immune geneexpression. We found that OspF, an injected virulencefactor previously identified as a repressor of immunegene expression, targets the chromatin reader HP1γ.Heterochromatin Protein 1 family members specificallyrecognize and bind histone H3 methylated at Lys 9.Although initially identified as chromatin-associatedtranscriptional silencers in heterochromatin, theirlocation in euchromatin indicates an active role in geneexpression. Notably, HP1γ phosphorylation at Serine83 defines a subpopulation exclusively located toeuchromatin, targeted to the site of transcriptionalelongation. We showed that OspF directly interactswith HP1γ, and causes HP1 dephosphorylation,suggesting a model in which this virulence effector“uses” HP1 proteins as beacons to target and repressimmune gene expression (Harouz, et al. EMBO J(2014)). OspF alters HP1γ phosphorylation mainly byinactivating the Erk-activated kinase MSK1,spotlighting it as a new HP1 kinase. In vivo, infectiousstresses trigger HP1γ phosphorylation in the colon,principally in the lamina propria and the intestinalcrypts. Several lines of evidence suggest that HP1proteins are modified as extensively as histones, anddecrypting the impact of these HP1 post-translationalmodifications on their transcriptional activities in vivowill be the next challenges to be taken up.