LAPTM5 Downregulation-Driven VAMP8 Phosphorylation Impairs Autophagosome-Lysosome Fusion and Aggravates Septic Acute Lung Injury.

Sepsis-induced acute lung injury (ALI) is a lethal inflammatory condition with limited therapeutic options. Macrophage autophagic homeostasis is essential to constrain septic ALI inflammation, though its upstream regulation remains elusive. Here, we report that lysosomal-associated protein transmembrane 5 (LAPTM5) is markedly downregulated in peripheral blood mononuclear cells (PBMCs) from septic ALI patients and alveolar macrophages (AMs) of septic mice, with its expression correlating inversely with the SOFA score. Macrophage-specific depletion of Laptm5 exacerbated mouse ALI symptoms, whereas AAV-mediated Laptm5 overexpression yielded diametrically opposite effects. Mechanistically, LPS stimulation promotes FOXB1 nuclear accumulation, which in turn represses the transcription and protein expression of LAPTM5. Furthermore, LAPTM5 acts as a molecular scaffold bridging PGAM5 and VAMP8, mediating PGAM5-dependent VAMP8 dephosphorylation to promote autophagosome-lysosome fusion and autophagic flux. This cascade clears damaged mitochondria, thereby mitigating intracellular oxidative stress and inflammation. This study defines macrophage LAPTM5 as a critical autophagy regulator that mitigates septic ALI, providing a potential avenue for future therapeutic exploration.