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

  • Commun Biol. 2026 Jun 25. doi: 10.1038/s42003-026-10543-y.
Xiaoyu Liu  #  1  2  3 ,  Daniel L Clemens  #  4 ,  Bai-Yu Lee  #  4 ,  Xian Xia  2  3  5 ,  Hongcheng Fan  2  3 ,  Kaelyn Y Feng  2  3 ,  Marcus A Horwitz  6  7 ,  Z Hong Zhou  8  9
Affiliations
  • 1. School of Life Sciences, Central China Normal University, Wuhan, China.
  • 2. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • 3. The California NanoSystems Institute (CNSI), UCLA, Los Angeles, CA, USA.
  • 4. Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • 5. State Key Laboratory of Virology and Biosafety, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China.
  • 6. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. [email protected].
  • 7. Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. [email protected].
  • 8. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. [email protected].
  • 9. The California NanoSystems Institute (CNSI), UCLA, Los Angeles, CA, USA. [email protected].
  • # Contributed equally.
PMID: 42350775 DOI: 10.1038/s42003-026-10543-y
Abstract

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.

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