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<p>Periodontal pathogen <i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>) is believed to possess immune evasion capabilities, but it remains unclear whether this immune evasion is related to host gene alternative splicing (AS). In this study, RNA-sequencing revealed significant changes in both AS landscape and transcriptomic profile of macrophages following <i>P. gingivalis</i> infection with/without knockout of gingipain (a unique toxic protease of <i>P. gingivalis</i>). <i>P. gingivalis</i> infection increased the PD-L1 transcripts expression and selectively upregulated a specific coding isoform that more effectively binds to PD-1 on T cells, thereby inhibiting immune function. Biological experiments also detected AS switch of PD-L1 in <i>P. gingivalis</i>-infected or gingipain-treated macrophages. AlphaFold 3 predictions indicated that the protein docking compatibility between PD-1 and <i>P. gingivalis</i>-upregulated PD-L1 isoform was over 80% higher than another coding isoform. These findings suggest that <i>P. gingivalis</i> employs gingipain to modulate the AS of PD-L1, facilitating immune evasion.</p>

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Gingipain regulates isoform switches of PD-L1 in macrophages infected with Porphyromonas gingivalis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月26日

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  • Yilin Zheng,
  • Ziyi Wang,
  • Yao Weng,
  • Heriati Sitosari,
  • Yuhan He,
  • Xiu Zhang,
  • Noriko Shiotsu,
  • Yoko Fukuhara,
  • Mika Ikegame,
  • Hirohiko Okamura

摘要

Periodontal pathogen Porphyromonas gingivalis (P. gingivalis) is believed to possess immune evasion capabilities, but it remains unclear whether this immune evasion is related to host gene alternative splicing (AS). In this study, RNA-sequencing revealed significant changes in both AS landscape and transcriptomic profile of macrophages following P. gingivalis infection with/without knockout of gingipain (a unique toxic protease of P. gingivalis). P. gingivalis infection increased the PD-L1 transcripts expression and selectively upregulated a specific coding isoform that more effectively binds to PD-1 on T cells, thereby inhibiting immune function. Biological experiments also detected AS switch of PD-L1 in P. gingivalis-infected or gingipain-treated macrophages. AlphaFold 3 predictions indicated that the protein docking compatibility between PD-1 and P. gingivalis-upregulated PD-L1 isoform was over 80% higher than another coding isoform. These findings suggest that P. gingivalis employs gingipain to modulate the AS of PD-L1, facilitating immune evasion.