Numerical data underlying Figs 1, 2, S1 and S2.

Lipoproteins of the opportunistic pathogen Staphylococcus aureus play a crucial role in various cellular processes and host interactions. Consisting of a protein and a lipid moiety, they support nutrient acquisition and anchor the protein to the bacterial membrane. Recently, we identified several processed and secreted small linear peptides that derive from the secretion signal sequence of S. aureus lipoproteins. Here, we show, for the first time, that the protein moiety of the S. aureus lipoprotein CamS has a biological role that is distinct from its associated linear peptide staph-cAM373. The small peptide was shown to be involved in interspecies horizontal gene transfer, the primary mechanism for the dissemination of antibiotic resistance among bacteria. We provide evidence that the CamS protein moiety is a potent repressor of cytotoxins, such as α-toxin and leukocidins. The CamS-mediated suppression of toxin transcription was reflected by altered disease severity in in vivo infection models involving skin and soft tissue, as well as bloodstream infections. Collectively, we have uncovered the role of the protein moiety of the staphylococcal lipoprotein CamS as a previously uncharacterized repressor of S. aureus toxin production, which consequently regulates virulence and disease outcomes. Notably, the camS gene is conserved in S. aureus, and we also demonstrated the muted transcriptional response of cytotoxins in 2 different S. aureus lineages. Our findings provide the first evidence of distinct biological functions of the protein moiety and its associated linear peptide for a specific lipoprotein. Therefore, lipoproteins in S. aureus consist of 3 functional components: a lipid moiety, a protein moiety, and a small linear peptide, with putative different biological roles that might not only determine the outcome of host–pathogen interactions but also drive the acquisition of antibiotic resistance determinants.机会致病菌金黄色葡萄球菌（Staphylococcus aureus）的脂蛋白（lipoprotein）在诸多细胞进程与宿主互作过程中发挥关键作用。该类脂蛋白由蛋白组分与脂质组分（lipid moiety）构成，既可辅助营养摄取，又能将蛋白锚定至细菌细胞膜。近期，本团队鉴定出数种源自金黄色葡萄球菌脂蛋白分泌信号序列（secretion signal sequence）的加工型分泌小线性肽。本研究首次证实，金黄色葡萄球菌脂蛋白CamS的蛋白组分，与其关联的线性肽staph-cAM373具备截然不同的生物学功能。已有研究证实，该小肽参与种间水平基因转移（interspecies horizontal gene transfer）——这是细菌间抗生素抗性（antibiotic resistance）传播的核心机制。本研究提供实验证据表明，CamS的蛋白组分是α-毒素（α-toxin）、杀白细胞素（leukocidins）等细胞毒素（cytotoxin）的强效抑制剂。CamS介导的毒素转录抑制效应，可通过皮肤软组织感染与血流感染等体内感染模型中疾病严重程度的变化得以体现。综上，本研究揭示了葡萄球菌脂蛋白CamS的蛋白组分作为此前未被表征的金黄色葡萄球菌毒素产生抑制剂的功能，进而调控细菌毒力与疾病转归。值得注意的是，camS基因在金黄色葡萄球菌中具有保守性，本研究同时证实，在两种不同的金黄色葡萄球菌谱系（lineage）中，细胞毒素的转录反应均被削弱。本研究成果首次为特定脂蛋白的蛋白组分与其关联线性肽存在差异化生物学功能提供了直接证据。据此，金黄色葡萄球菌的脂蛋白包含三类功能性组分：脂质组分、蛋白组分与小线性肽，三者推定具备不同生物学功能，不仅可能决定宿主-病原体互作的最终结局，还可推动抗生素抗性决定簇（antibiotic resistance determinants）的获取。