Keratin7 and Desmoplakin are involved in acute lung injury induced by sepsis through RAGE

Abstract

Keratin 7 (Krt7) is a member of the keratin family and is primarily involved in cytoskeleton composition. It has been shown that Krt7 is able to influence its own remodeling and interactions with other signaling molecules via phosphorylation at specific sites unique to Krt7. However, its molecular mechanism in acute lung injury (ALI) remains unclear. In this study, differential proteomics was used to analyze lung samples from the receptor for advanced glycation end products (RAGE)-deficient and (wild-type)WT-septic mice. We screened for the target protein Krt7 and identified Ser53 as the phosphorylation site using mass spectrometry (MS), and this phosphorylation further triggered the deformation and disintegration of Desmoplakin (Dsp), ultimately leading to epithelial barrier dysfunction. Furthermore, we demonstrated that in sepsis, mDia1/Cdc42/p38 MAPK signaling activation plays a role in septic lung injury. We also explored the mechanism of alveolar dysfunction of the Krt7-Dsp complex in the epithelial cell barrier. In summary, the present findings increase our understanding of the pathogenesis of septic acute lung injury.

Keywords: ALI; Desmoplakin; Hyperpermeability; Keratin7; RAGE; Sepsis.