Li Lanxin, Adamson Christopher, Ng Evan Wei Long, Qiao Yuan
School of Chemistry, Chemical Engineering and Biotechnology (CCEB), Nanyang Technological University (NTU), 21 Nanyang Link, Singapore, 637371, Singapore.
Nat Commun. 2025 Jul 22;16(1):6737. doi: 10.1038/s41467-025-62097-y.
Gut microbiota-derived peptidoglycan fragments (PGNs) are potent inducers of Candida albicans hyphal growth, a key virulence trait for C. albicans pathogenesis in hosts. Herein, we identify the C. albicans oligopeptide transporter 4 (Opt4) as the long-sought major transporter responsible for internalizing a diverse range of natural PGNs into fungal cells. However, contrary to the conventional view, we reveal that blocking the cellular uptake of PGNs does not prevent C. albicans hyphal growth. Instead, we discover that extracellular sensing of PGNs by C. albicans cell surface protein Ssy1 is essential for activating the downstream cAMP-PKA pathway in hyphal signaling. Importantly, the ssy1Δ/Δ mutant, which is defective in PGN-induced hyphal growth, remains unresponsive to the β-lactam-induced PGN storm in the mouse gut. It predominantly maintains yeast morphology and shows no sign of systemic dissemination. These findings establish Ssy1 as a potential anti-virulence target for preventing PGN-induced invasive growth of C. albicans in hosts.
肠道微生物群衍生的肽聚糖片段（PGNs）是白色念珠菌菌丝生长的有效诱导剂，而菌丝生长是白色念珠菌在宿主体内致病的关键毒力特征。在此，我们确定白色念珠菌寡肽转运蛋白4（Opt4）是长期以来寻找的主要转运蛋白，负责将多种天然PGNs内化到真菌细胞中。然而，与传统观点相反，我们发现阻断PGNs的细胞摄取并不能阻止白色念珠菌的菌丝生长。相反，我们发现白色念珠菌细胞表面蛋白Ssy1对PGNs的细胞外感知对于激活菌丝信号传导中的下游cAMP-PKA途径至关重要。重要的是，在PGN诱导的菌丝生长中存在缺陷的ssy1Δ/Δ突变体，对小鼠肠道中β-内酰胺诱导的PGN风暴仍无反应。它主要维持酵母形态，没有全身播散的迹象。这些发现确立了Ssy1作为预防PGN诱导的白色念珠菌在宿主体内侵袭性生长的潜在抗毒力靶点。
