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

Lulu Sun, Sijin Wu, Hui Wang, Tianyu Zhang, Mengyu Zhang, Xuepeng Bai, Xiumei Zhang, Bingqing Li, Cai Zhang, Yan Li, Jun Zhou () and Tianliang Li ()
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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
Tianliang Li: Shandong Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54377-w

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