The desmoplakin-intermediate filament linkage regulates cell mechanics

Area of Science:

• Cell Biology
• Biophysics
• Biochemistry

Background:

• Mechanical forces are translated into biochemical signals, crucial for tissue development and homeostasis.
• Dysregulation of this mechanotransduction process is implicated in diseases like cancer and cardiovascular disorders.
• While the actin cytoskeleton's role in mechanosensing is known, the desmosome-intermediate filament (DSM-IF) network's contribution remains unclear.

Purpose of the Study:

• To investigate the role of the desmosome-intermediate filament (DSM-IF) network in cellular mechanics and mechanotransduction.
• To determine how modulating the DSM-IF interaction affects cell forces and stiffness.
• To understand the interplay between the DSM-IF network and the actin cytoskeleton in regulating cell mechanics.

Main Methods:

• Utilized mutant forms of desmoplakin to alter the interaction between desmosomes (DSMs) and intermediate filaments (IFs).
• Employed micropillar arrays and atomic force microscopy to measure cell-substrate and cell-cell forces and cell stiffness.
• Disrupted the actin cytoskeleton to assess its influence on DSM-IF-mediated mechanical changes.

Main Results:

• Strengthening the DSM-IF interaction significantly increased cell-substrate forces, cell-cell forces, and cell stiffness in both cell pairs and sheets.
• Disrupting the DSM-IF interaction led to a decrease in these measured forces and stiffness.
• These mechanical alterations induced by DSM-IF modulation were abolished upon disruption of the actin cytoskeleton.

Conclusions:

• The desmosome-intermediate filament (DSM-IF) network plays a critical role in regulating cell mechanics and tissue stiffness.
• Modulating the DSM-IF interaction provides a mechanism to control cell forces and stiffness, with implications for tissue homeostasis.
• The findings highlight the importance of balancing forces among cytoskeletal systems, with tissue-specific DSM-IF composition offering a way to differentially regulate tissue mechanics.