Biochimica et biophysica acta. Molecular basis of disease · 2026
Dysregulation of the CUL2-Sirt2 axis exacerbates lung epithelial barrier injury in Staphylococcus aureus-induced pneumonia.
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Zhou Xiangyu, Zhao Zhuyun, Wang Ke
Аннотация
BACKGROUND: Staphylococcus aureus infection can cause severe lung injury and inflammation, with mechanisms including excessive activation of the NF-κB pathway and disruption of the epithelial barrier. The role of host regulatory factors in this process remains unclear.
METHODS: This study used Sirt2 gene knockout (Sirt2-/-), adeno-associated virus-mediated overexpression (AAV-Sirt2) mouse models, and Sirt2-silenced cells to evaluate lung injury, inflammatory factors, and tight junction protein changes. Western blot, immunofluorescence, and immunoprecipitation were employed to investigate the molecular mechanisms.
RESULTS: Sirt2 deficiency exacerbates lung injury, enhances NF-κB activation, and decreases the levels of Occludin, Claudin-1, and ZO-1. Conversely, Sirt2 overexpression alleviates the damage, suppresses inflammation, and restores barrier protein expression. Mechanistically, Sirt2 undergoes proteasomal degradation through CUL2-mediated K48-linked ubiquitination, and silencing CUL2 stabilizes Sirt2, reducing inflammation.
CONCLUSION: Sirt2 protects lung function by inhibiting the NF-κB pathway and maintaining barrier protein expression. The CUL2-Sirt2 axis may provide a new mechanistic insight for understanding infectious lung injury.
METHODS: This study used Sirt2 gene knockout (Sirt2-/-), adeno-associated virus-mediated overexpression (AAV-Sirt2) mouse models, and Sirt2-silenced cells to evaluate lung injury, inflammatory factors, and tight junction protein changes. Western blot, immunofluorescence, and immunoprecipitation were employed to investigate the molecular mechanisms.
RESULTS: Sirt2 deficiency exacerbates lung injury, enhances NF-κB activation, and decreases the levels of Occludin, Claudin-1, and ZO-1. Conversely, Sirt2 overexpression alleviates the damage, suppresses inflammation, and restores barrier protein expression. Mechanistically, Sirt2 undergoes proteasomal degradation through CUL2-mediated K48-linked ubiquitination, and silencing CUL2 stabilizes Sirt2, reducing inflammation.
CONCLUSION: Sirt2 protects lung function by inhibiting the NF-κB pathway and maintaining barrier protein expression. The CUL2-Sirt2 axis may provide a new mechanistic insight for understanding infectious lung injury.