HSP27 regulates force-coordinated DDR1 condensate disassembly and liquid-to-gel phase transition

Area of Science:

• Cardiovascular Biology
• Cellular Mechanotransduction
• Molecular Signaling

Background:

• Endothelial cell (EC) mechanosensing of blood flow is critical for vascular health and atherosclerosis.
• Discoidin domain receptor 1 (DDR1) functions as a mechanosensor, translating shear stress into cellular signals.
• The precise mechanisms by which shear stress patterns influence EC signaling via DDR1 remain incompletely understood.

Purpose of the Study:

• To investigate the role of heat shock protein 27 (HSP27) in regulating DDR1 mechanosensing and endothelial responses to shear stress.
• To elucidate the DDR1-HSP27 axis in the context of endothelial YAP activation and atherogenesis.

Main Methods:

• Utilized cell culture models to study endothelial cell responses to varying shear stress conditions.
• Investigated protein-protein interactions and post-translational modifications involving DDR1 and HSP27.
• Examined the impact of the DDR1-HSP27 axis on YAP signaling and in vivo models of atherosclerosis.

Main Results:

• Laminar shear stress induces transient DDR1 condensation via liquid-liquid phase separation, while atherogenic shear causes sustained condensation.
• HSP27 regulates shear-dependent DDR1 condensation and phase transition, with its interaction with DDR1 being crucial for condensate disassembly.
• Atherogenic shear promotes DDR1-mediated HSP27 phosphorylation, leading to DDR1 gel transition and subsequent YAP activation.

Conclusions:

• The DDR1-HSP27 axis is a key regulator of endothelial YAP activation in response to atherogenic shear stress.
• This pathway plays a significant role in the development of atherosclerosis in vivo.
• Targeting the DDR1-HSP27 interaction presents a potential therapeutic strategy for preventing endothelial dysfunction and atherosclerosis.