bioRxiv · 10.1101/264184
Targeting redox regulatory site of protein kinase B impedes neutrophilic inflammation
Abstract
Neutrophil activation has a pathogenic effect in inflammatory diseases. Protein kinase B (PKB)/AKT regulates diverse cellular responses. However, the significance of AKT in neutrophilic inflammation is still not well understood. Here, we identified CLLV-1 as a novel AKT inhibitor. CLLV-1 inhibited respiratory burst, degranulation, chemotaxis, and AKT phosphorylation in activated human neutrophils and dHL-60 cells. Significantly, CLLV-1 blocked AKT activity and covalently reacted with AKT Cys310 in vitro. The AKT309-313 peptide-CLLV-1 adducts were determined by NMR or mass spectrometry assay. The alkylation agent-conjugated AKT (reduced form) level was also inhibited by CLLV-1. Additionally, CLLV-1 ameliorated lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. CLLV-1 acts as a covalent allosteric AKT inhibitor by targeting AKT Cys310 to restrain inflammatory responses in human neutrophils and LPS-induced ALI in vivo. Our findings provide a mechanistic framework for redox modification of AKT that may serve as a novel pharmacological target to alleviate neutrophilic inflammation.
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Hwang, T.-L., Chen, P.-J., Ko, I.-L., Lee, C.-L., Hu, H.-C., Chang, F.-R., Wu, Y.-C., Leu, Y.-L., Wu, C.-C., Tsai, Y.-F., Lin, C.-Y., Pan, C.-Y.. 2018-02-13. Targeting redox regulatory site of protein kinase B impedes neutrophilic inflammation. https://doi.org/10.1101/264184
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