Park Youngseon, Sisley Tyler A, Stone Madeleine C, Corrigan Rebecca M, Vickery Christopher R, Gründling Angelika, Walker Suzanne
Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
Section of Molecular Microbiology and Centre for Bacterial Resistance Biology, Department of Infectious Disease, Imperial College London, London SW7 2AZ, United Kingdom.
Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2426464122. doi: 10.1073/pnas.2426464122. Epub 2025 Jun 30.
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 (), a polytopic membrane protein similar to a eukaryotic CAAX protease, as a factor that controls LTA levels in 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 (ignal eptidase egulator).
是一种革兰氏阳性病原体，可引发危及生命的感染。其细胞包膜含有称为磷壁酸的阴离子聚合物，这是细胞存活所必需的。磷壁酸有两种形式，由不同的生物合成途径产生。一种形式是脂磷壁酸（LTA），锚定在细胞膜中；另一种形式是壁磷壁酸（WTA），与肽聚糖细胞壁共价连接。尽管LTA和WTA生物合成途径已被阐明，但磷壁酸产生的调控仍未得到充分理解。在这里，我们鉴定出SpbR（），一种类似于真核CAAX蛋白酶的多聚体膜蛋白，作为控制细胞中LTA水平的一个因子。我们表明，SpbR的缺失会导致短的LTA，并且在阻止WTA生物合成时会出现合成病态表型，而过度表达SpbR会导致LTA延长。从机制上讲，我们发现SpbR与I型信号肽酶SpsB发生物理结合，SpsB可切割LtaS，LtaS是在细胞膜外侧组装LTA的聚合酶，并且我们表明这种物理相互作用在体内和体外均抑制SpsB对LtaS的切割。尽管这里研究的表型主要由SpbR对LtaS的作用主导，但它也抑制其他SpsB底物的切割。基于其在调节SpsB活性中的作用，我们将这个因子命名为SpbR（信号肽酶调节剂）。
