Post-transcriptional regulation of the heme assimilation system (Has) fine-tunes extracellular heme sensing.

is an opportunistic pathogen that utilizes heme as a primary iron source within the host. Extracellular heme is sensed via a heme assimilation system () that encodes an extracytoplasmic function (ECF) σ factor system. Herein, using deletion mutants, quantitative PCR analyses, and immunoblotting, we show that the activation of the σ factor HasI requires heme release from the hemophore HasAp to the outer-membrane receptor HasR. Using RT-PCR and 5'-RACE, we observed that following transcriptional activation of the co-transcribed , it is further processed into specific mRNAs varying in stability. We noted that the processing and variation in stability of the and mRNAs in response to heme provide a mechanism for differential expression from co-transcribed genes. The multiple layers of post-transcriptional regulation of the ECF signaling cascade, including the previously reported post-transcriptional regulation of HasAp by the heme metabolites biliverdin IXβ and IXδ, allow fine-tuning of the cell-surface signaling system in response to extracellular heme levels. We hypothesize that the complex post-transcriptional regulation of the Has system provides an advantage in colonizing a variety of physiological niches in the host.