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PDCD6 modulates LC3-associated phagocytosis-mediated antimicrobial defense by regulating lactate metabolism

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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Sun Lulu

LAB HEAD: Tianliang Li

PROVIDER: PXD056047 | Pride | 2024-10-18

REPOSITORIES: Pride

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Project description:Background: In acute kidney injury, macrophages play a major role in regulating inflammation. Classically activated macrophages (M1) undergo drastic metabolic reprogramming during their differentiation and upregulate the aerobic glycolysis pathway to fulfill their pro-inflammatory functions. NAD+ regeneration is crucial for the maintenance of glycolysis and the most direct pathway by which this occurs is via the fermentation of pyruvate to lactate, catalyzed by lactate dehydrogenase A (LDHA). Our previous study determined that LDHA is predominantly expressed in the proximal segments of the nephron in the mouse kidney and increases with hypoxia. This study investigates the potential of LDHA as a therapeutic target for inflammation by exploring its role in macrophage function in vitro. Methods: Bone-marrow-derived macrophages (BMDMs) were isolated from myeloid-specific LDHA knockout mice derived from crossbreeding LysM-Cre transgenic mice and LDHA floxed mice. RNA sequencing and LC-MS/MS metabolomics analyses were used in this study to determine the effect of LDHA deletion on BMDM following stimulation with IFN-γ. Results: LDHA deletion in IFN-γ BMDMs resulted in a significant alteration of the macrophage activation and functional pathways, and change in glycolytic, cytokine, and chemokine gene expression. Metabolite concentrations associated with pro-inflammatory macrophage profiles were diminished while anti-inflammatory-associated ones were increased in LDHA KO BMDMs. Glutamate and amino sugars metabolic pathways were significantly affected by the LDHA deletion. A combined muti-omics analysis highlighted changes in Rap1 signaling, cytokine-cytokine receptor interaction, focal adhesion, and MAPK signaling metabolism pathways. Conclusions: Deletion of LDHA in macrophages results in a notable reduction in the pro-inflammatory profile and concurrent upregulation of anti-inflammatory pathways. These findings suggest that LDHA could serve as a promising therapeutic target for inflammation, a key contributor to the pathogenesis of acute kidney injury.

			Action	DRS
	GE015GI_EV.msf	Msf
	GE015GI_EV.raw	Raw
	GE015GI_PDCD6.msf	Msf
	GE015GI_PDCD6.raw	Raw
	checksum.txt	Txt

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PDCD6 modulates LC3-associated phagocytosis-mediated antimicrobial defense by regulating lactate metabolism

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