Porphyromonas gingivalis induction of TLR2 association with Vinculin enables PI3K activation and immune evasion

Karthikeyan Pandi, Sarah Angabo, Jeba Gnanasekaran, Hasnaa Makkawi, Luba Eli-Berchoer, Fabian Glaser, Gabriel Nussbaum

Research output: Contribution to journalArticlepeer-review

Abstract

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that thrives in the inflamed environment of the gingival crevice, and is strongly associated with periodontal disease. The host response to P. gingivalis requires TLR2, however P. gingivalis benefits from TLR2-driven signaling via activation of PI3K. We studied TLR2 protein-protein interactions induced in response to P. gingivalis, and identified an interaction between TLR2 and the cytoskeletal protein vinculin (VCL), confirmed using a split-ubiquitin system. Computational modeling predicted critical TLR2 residues governing the physical association with VCL, and mutagenesis of interface residues W684 and F719, abrogated the TLR2-VCL interaction. In macrophages, VCL knock-down led to increased cytokine production, and enhanced PI3K signaling in response to P. gingivalis infection, effects that correlated with increased intracellular bacterial survival. Mechanistically, VCL suppressed TLR2 activation of PI3K by associating with its substrate PIP2. P. gingivalis induction of TLR2-VCL led to PIP2 release from VCL, enabling PI3K activation via TLR2. These results highlight the complexity of TLR signaling, and the importance of discovering protein-protein interactions that contribute to the outcome of infection.

Original languageAmerican English
Article numbere1011284
JournalPLoS Pathogens
Volume19
Issue number4
DOIs
StatePublished - Apr 2023

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Virology
  • Parasitology
  • Microbiology
  • Immunology

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