SpbR controls lipoteichoic acid length by directly inhibiting signal peptidase SpsB in Staphylococcus aureus

• 成果类型: Article
• 署名作者: Park, Youngseon; Sisley, Tyler A.; Stone, Madeleine C.; Corrigan, Rebecca M.; Vickery, Christopher R.; Gruendling, Angelika; Walker, Suzanne
• 署名单位: University College Dublin; Harvard University; Harvard Medical School; Imperial College London; Imperial College London
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8716
• DOI: 10.1073/pnas.2426464122
• 发表日期: 2025-07-08
• 关键词: wall teichoic-acid; regulated intramembrane proteolysis; domain-containing proteins; cell-wall; vitro reconstitution; bacillus-subtilis; antimicrobial peptides; glycerol phosphate; membrane-protein; biosynthesis

摘要

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 by different biosynthetic pathways. One form, lipoteichoic acid (LTA), is anchored in the cell membrane; the other form, wall teichoic acid (WTA), is covalently linked to the peptidoglycan cell wall. Although the LTA and WTA biosynthetic pathways have been characterized, regulation of teichoic acid production is not well understood. Here, we identified SpbR (SAOUHSC_00965), a polytopic membrane protein similar to a eukaryotic CAAX protease, as a factor that controls LTA levels in S. aureus cells. We show that loss of SpbR results in short LTAs and a synthetically sick phenotype when WTA biosynthesis is prevented, whereas overexpressing SpbR results in elongated LTAs. 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 SpbR's effects on LtaS, it also inhibits cleavage of other SpsB substrates. Based on its role in regulating the activity of SpsB, we named this factor SpbR (Signal peptidase b Regulator).