Lactate-driven ATP6V1B2 lactylation triggers asthmatic inflammation by linking lysosomal dysfunction to mitochondrial...

Area of Science:

• Immunology
• Metabolic pathways
• Cellular biology

Background:

• Immunometabolic reprogramming drives asthma pathogenesis.
• Molecular links between lactate, airway inflammation, and protein lactylation (Kla) are unclear.
• ATP6V1B2 is a key V-ATPase subunit implicated in cellular processes.

Purpose of the Study:

• To elucidate the molecular mechanisms linking lactate accumulation to airway inflammation via protein lactylation.
• To identify key lactylation targets in asthma.
• To investigate the role of ATP6V1B2 lactylation in asthma pathogenesis.

Main Methods:

• House dust mite (HDM)-induced asthma model.
• Quantitative lactylomics.
• Molecular dynamics simulations and biochemical analyses.
• Validation in primary human bronchial epithelial cells (HBEs).
• In vivo studies using AAV-delivered lactylation-deficient mutant.

Main Results:

• ATP6V1B2 identified as a core lactylation target, with lactylation occurring at K108/K109.
• Lactylation restricts ATP6V1B2 flexibility, disassembles the V1-V0 complex, and impairs proton pump activity.
• This leads to lysosomal alkalinization, membrane permeabilization (LMP), mitochondrial ROS burst, and pyroptosis via a Caspase-8/3/GSDME pathway.
• Blocking ATP6V1B2 lactylation in vivo attenuated airway inflammation, Th2 cytokine release, and pyroptosis.

Conclusions:

• A novel "l-lactate-ATP6V1B2-GSDME" axis is characterized.
• ATP6V1B2 lactylation acts as a critical metabolic switch linking lysosomal damage to inflammatory cell death.
• Targeting ATP6V1B2 lactylation offers a potential therapeutic strategy for metabolic dysregulation in severe chronic asthma.