SpbR is a Direct Regulator of Signal Peptidase SpsB that Controls Lipoteichoic Acid Length in Staphylococcus aureus

Staphylococcus aureus is a Gram-positive pathogen that causes life threatening infections. Its cell envelope contains anionic polymers called teichoic acids that are required for cell viability. Teichoic acids come in two forms and are made in S. aureus by different biosynthetic pathways. One form, lipoteichoic acid (LTA), is anchored in the cell membrane; the other, wall teichoic acid (WTA), is covalently linked to the peptidoglycan cell wall. Although the biosynthetic pathways for LTA and WTA have been characterized, regulatory mechanisms that control teichoic acid production are not well understood. Here, we identify SpbR (SAOUHSC_00965), a polytopic membrane protein similar to a eukaryotic CAAX protease, as a new factor that controls LTA levels in S. aureus cells. We show that loss of this factor results in short LTAs and a synthetically sick phenotype when WTA biosynthesis is prevented, whereas overexpressing this factor results in LTAs that are longer than normal. Mechanistically, we find that SpbR physically associates with the type I signal peptidase SpsB, which cleaves LtaS, the polymerase that assembles LTA on the extracellular side of the membrane. and we show that this physical interaction inhibits SpsB cleavage of LtaS both in vivo and in vitro. Although the phenotypes investigated here are dominated by effects of SpbR on LtaS, we find that this factor also inhibits cleavage of other SpsB substrates. Based on its role in regulating the activity of SpsB, we named this factor SpbR (for Signal peptidase b Regulator). To the best of our knowledge, SpbR is the first identified example of a direct regulator of a type I signal peptidase in bacteria.