Fur regulates expression of the Salmonella pathogenicity island 1 type III secretion system through HilD

The invasion of intestinal epithelial cells by Salmonella enterica serovar Typhimurium is mediated by a type III secretion system (T3SS) encoded on Salmonella pathogenicity island 1 (SPIT). Expression of the SPIT T3SS is tightly regulated by the combined action of HilC, HilD, and RtsA, three AraC family members that can independently activate hilA, which encodes the direct regulator of the SPIT structural genes. Expression of hilC, hill), and rtsA is controlled by a number of regulators that respond to a variety of environmental signals. In this work, we show that one such signal is iron mediated by Fur (ferric uptake regulator). Fur activates hilA transcription in a HilD-dependent manner. Fur regulation of Hill) does not appear to be simply at the transcriptional or translational level but rather requires the presence of the Hill) protein. Fur activation of SPIT is not mediated through the Fur-regulated small RNAs RfrA and RfrB, which are the Salmonella ortholog and paralog of RyhB that control expression of sodB. Fur regulation of Hill) is also not mediated through the known SPIT repressor HiIE or the CsrABC system. Although understanding the direct mechanism of Fur action on Hill) requires further analysis, this work is an important step toward elucidating how various global regulatory systems control SPI1.