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Updated: Sep 29, 2026
Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
LAPTM5 Downregulation-Driven VAMP8 Phosphorylation Impairs Autophagosome-Lysosome Fusion and Aggravates Septic Acute
Lang Jiang1, Qilan Li1, Hao Liu2
1Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
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.
