Insulin alleviates LPS-induced ARDS via inhibiting CUL4B-mediated proteasomal degradation and restoring expression level of Na,K-ATPase α1 subunit through elevating HCF-1

• Published in: Biochemical and biophysical research communications 2022-06, Vol.611, p.60-67
• Main Authors: Huang, Xue-Ting, Zheng, Yu, Long, Guo, Peng, Wei-Ting, Wan, Qi-Quan
• Format: Article
• Language: English
• Subjects: Acute respiratory distress syndrome; ATP1A1; CUL4B; Cullin Proteins - metabolism; E3 ligase; Humans; Insulin; Insulin - metabolism; Lipopolysaccharides - metabolism; Na,K-ATPase; Pulmonary Alveoli - metabolism; Respiratory Distress Syndrome - drug therapy; Sodium-Potassium-Exchanging ATPase - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.04.044

Acute respiratory distress syndrome (ARDS) is a critical disease with a high mortality rate, characterized by obstinate hypoxemia caused by accumulation of alveolar fluid and excessive uncontrolled inflammation. Na,K-ATPase α1 (ATP1A1) subunit is an important component of Na,K-ATPase that transports Na+ and K+ and scavenges alveolar fluid. The function of Na,K-ATPase is always impaired during ARDS and results in more severe symptoms of ARDS. However, the regulatory mechanism of Na,K-ATPase after ARDS remains unclear. Here, we revealed ATP1A1 was downregulated post-transcriptionally by an E3 ligase component CUL4B mediated proteasomal degradation. Moreover, we found insulin could inhibit the upregulation of CUL4B in an insulin receptor cofactor HCF-1-dependent manner. Our study resolved the molecular mechanism underlying the clearance impairment of alveolar fluid and provided a clue for the usage of insulin as a potential therapeutic medicine for ARDS. [Display omitted] •CUL4B directly interacted with Na,K-ATPase α1 subunit in vivo.•Insulin effectively inhibited the upregulation of an E3 ligase component CUL4B caused by LPS.•CUL4B downregulated Na,K-ATPase α1 subunit post-transcriptionally via proteasomal degradation.