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<p><i>Francisella tularensis</i>, a gram-negative facultative intracellular pathogen, causes the often-fatal disease tularemia. Its <i>Francisella</i> pathogenicity island (FPI) encodes a type VI secretion system (T6SS) critical for virulence, yet the mechanisms by which T6SS effectors enable intracellular replication remain poorly understood. Here, we report the structure of the T6SS effector PdpC, revealing a novel protein fold with no identifiable homologs. The structure resembles a seahorse, comprising five domains: an N-terminal domain, a central body domain (CBD), a wedge domain, a C-terminal tail, and an unmodeled “mouth” domain. Biochemical analyses demonstrate that PdpC binds host phospholipids, particularly phosphatidylinositol-3-phosphate, and interacts with PdpE, another FPI-encoded protein. Structure-guided functional studies show that the CBD alone suffices for these interactions, while PdpE is secreted via a T6SS-independent pathway. These findings explain how the sophisticated effector duo enables phagosomal escape and establishes infection: PdpC is delivered by T6SS to PI(3)P-enriched early phagosomal membranes to rupture phagosomes to escape, and then coordinates with PdpE to promote intracytoplasmic <i>Francisella</i> replication. This work transforms PdpC from an orphan virulence factor into a tractable molecular switch at the heart of <i>Francisella</i>’s intracellular lifestyle and a potential target for anti-tularemia therapeutics.</p>

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Structure and potential role of T6SS effector PdpC in Francisella tularensis intracellular lifestyle

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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  • Xiaoyu Liu,
  • Daniel L. Clemens,
  • Bai-Yu Lee,
  • Xian Xia,
  • Hongcheng Fan,
  • Kaelyn Y. Feng,
  • Marcus A. Horwitz,
  • Z. Hong Zhou

摘要

Francisella tularensis, a gram-negative facultative intracellular pathogen, causes the often-fatal disease tularemia. Its Francisella pathogenicity island (FPI) encodes a type VI secretion system (T6SS) critical for virulence, yet the mechanisms by which T6SS effectors enable intracellular replication remain poorly understood. Here, we report the structure of the T6SS effector PdpC, revealing a novel protein fold with no identifiable homologs. The structure resembles a seahorse, comprising five domains: an N-terminal domain, a central body domain (CBD), a wedge domain, a C-terminal tail, and an unmodeled “mouth” domain. Biochemical analyses demonstrate that PdpC binds host phospholipids, particularly phosphatidylinositol-3-phosphate, and interacts with PdpE, another FPI-encoded protein. Structure-guided functional studies show that the CBD alone suffices for these interactions, while PdpE is secreted via a T6SS-independent pathway. These findings explain how the sophisticated effector duo enables phagosomal escape and establishes infection: PdpC is delivered by T6SS to PI(3)P-enriched early phagosomal membranes to rupture phagosomes to escape, and then coordinates with PdpE to promote intracytoplasmic Francisella replication. This work transforms PdpC from an orphan virulence factor into a tractable molecular switch at the heart of Francisella’s intracellular lifestyle and a potential target for anti-tularemia therapeutics.