Activation of PDZ-Binding Kinase Contributes to Airway Remodeling in Asthma

Airway remodeling is an important pathological feature of refractory asthma. PDZ-binding kinase (PBK), as a serine/threonine protein kinase, has been extensively studied in various biological processes. However, the role of PBK in airway smooth muscle cells (ASMCs) proliferation and airway remodeling remains unclear. In addition, sphingosine-1-phosphate (S1P) has been proven to play a key role in the progression of airway remodeling. The present study aims to investigate whether PBK mediates S1P-induced ASMCs proliferation and to elucidate the underlying molecular mechanisms.

Ovalbumin (OVA)-induced asthmatic rats and primary cultured ASMCs were employed in the study. Inflammatory factor production, airway resistance assessment, histological staining and immunohistochemical staining were conducted to evaluate the development of asthma. CCK-8 and EdU assays were used for the measurement of cell proliferation. Western blotting and Ubiquitination assay were used to detect protein expressions.

PBK was up-regulated in lungs of OVA-induced chronic asthmatic rats and mediated airway remodeling. Targeting PBK could alleviate airway wall thickness and ASMCs hyperplasia in asthma model. In cultured ASMCs, S1P reduced ubiquitin-mediated degradation of PBK by down-regulating STUB1 leading to PBK protein accumulation. Meanwhile, S1P induced PBK phosphorylation and activation, which further led to the activation of protein regulator of cytokinesis 1 (PRC1) by increasing its expression and phosphorylation, finally promoting ASMCs proliferation.

Activation of PBK contributes to ASMCs proliferation and airway remodeling in the development of asthma. S1P upregulates PBK expression by suppressing STUB1-mediated proteasome-degradation and elevates PBK activity through increasing its phosphorylation. Activation of PBK further stimulates PRC1 expression and phosphorylation leading to ASMCs proliferation. Targeting PBK might be an effective therapeutic strategy for asthma.