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PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense

Author

Listed:
  • Lulu Sun

    (Shandong Normal University)

  • Sijin Wu

    (Xi’an Jiaotong-Liverpool University)

  • Hui Wang

    (Shandong Normal University)

  • Tianyu Zhang

    (Shandong Normal University)

  • Mengyu Zhang

    (Shandong Normal University)

  • Xuepeng Bai

    (Public Health Clinical Center Affiliated to Shandong University)

  • Xiumei Zhang

    (Shandong First Medical University & Shandong Academy of Medical Sciences)

  • Bingqing Li

    (Shandong First Medical University & Shandong Academy of Medical Sciences)

  • Cai Zhang

    (Shandong University)

  • Yan Li

    (Shandong Normal University)

  • Jun Zhou

    (Shandong Normal University
    Nankai University)

  • Tianliang Li

    (Shandong Normal University)

Abstract

LC3-associated phagocytosis (LAP) is critical in host defense against invading pathogens, but the molecular mechanism for LAP activation is still unclear. Here, we find programmed cell death 6 (PDCD6) as a negative regulator of LAP. PDCD6 deficiency in mice and macrophages induces enhanced bactericidal activity and LAP formation. In parallel, lactate dehydrogenase A (LDHA) activity and lactate production is induced in macrophages challenged with bacteria, Zymosan or Pam3CSK4, while genetic ablation or pharmacological inhibition of LDHA reduces lactate levels and impairs bactericidal activity in vivo and in vitro. Mechanistically, PDCD6 interacts with LDHA to downregulate lactate metabolism, leading to reduced RUBCN lactylation at lysine33 (K33). By contrast, PDCD6-deficiency increases RUBCN lactylation, thereby promotes RUBCN interaction with VPS34, LAP formation, and protective responses. Our results thus suggest a PDCD6-LDHA-lactate-RUBCN axis of innate immunity regulation that may both contribute to protection from infectious diseases and serve as targets for therapeutic development.

Suggested Citation

  • Lulu Sun & Sijin Wu & Hui Wang & Tianyu Zhang & Mengyu Zhang & Xuepeng Bai & Xiumei Zhang & Bingqing Li & Cai Zhang & Yan Li & Jun Zhou & Tianliang Li, 2024. "PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54377-w
    DOI: 10.1038/s41467-024-54377-w
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