PDCD6 Regulates Lactate Metabolism to Modulate LC3-associated Phagocytosis and Antibacterial Defense

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Nov 23

PMID 39578445

Authors

Lulu Sun

Sijin Wu

Hui Wang

Tianyu Zhang

Mengyu Zhang

Xuepeng Bai

Xiumei Zhang

Bingqing Li

Cai Zhang

Yan Li

Jun Zhou

TianLiang Li

Affiliations

Soon will be listed here.

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.

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