FIG. 6.

Isd-mediated heme-iron uptake in S. aureus. A. The isd locus is comprised of isdA, isdB, and isdC, which encode cell wall-anchored proteins carrying LPKTG, LPQTG, and NPQTN motifs in their respective sorting signals. Located elsewhere in the S. aureus genome, isdH and isdI encode a fourth LPKTG surface protein and a heme oxygenase, respectively. All isd genes are regulated by the ferric uptake repressor (Fur), which represses transcription under iron-replete conditions by binding to fur boxes present in promoter regions (shaded boxes). Arrows indicate the direction of transcription. B. A model for Isd-mediated heme-iron transport across the cell wall of S. aureus. IsdA, IsdB, and IsdH are anchored to the cell wall by sortase A and function as receptors for hemoprotein ligands, including haptoglobin (Hpt), hemoglobin (Hb), or heme. Upon binding to Isd receptors, heme is released from the hemoproteins by an as-yet-undefined mechanism and passaged through the cell wall in an IsdC-dependent manner. Treatment of staphylococcal cells with extracellular proteinase K completely degrades IsdB, only partially digests IsdA, and leaves IsdC intact, suggesting different degrees of surface exposure for each of these cell wall proteins. The heme molecule is then transported through the membrane transport system composed of IsdDEF into the cytoplasm. Upon entry into the cytoplasm, heme is degraded by IsdG and IsdI heme monooxygenases. This leads to the release of free iron for use by the bacterium as a nutrient source. (Adapted from reference 182 with permission from Elsevier.)