Gene

Nuclear matrix

Biophysics

Actin

Cytoskeleton

Cell

Focal adhesion

Lamin

Mechanotransduction

Chemistry

Plectin

Nucleus

Stress fiber

Nuclear protein

Genetics

Biochemistry

Signal transduction

Intermediate filament

Keratin

Chromatin

Transcription factor

Biology

Nuclear lamina

Cell biology

Science Advances

The keratin network of intermediate filaments provides keratinocytes with essential mechanical strength and resilience, but the contribution to mechanosensing remains poorly understood. Here, we investigated the role of the keratin cytoskeleton in the response to altered matrix rigidity. We found that keratinocytes adapted to increasing matrix stiffness by forming a rigid, interconnected network of keratin bundles, in conjunction with F-actin stress fiber formation and increased cell stiffness. Disruption of keratin stability by overexpression of the dominant keratin 14 mutation R416P inhibited the normal mechanical response to substrate rigidity, reducing F-actin stress fibers and cell stiffness. The R416P mutation also impaired mechanotransduction to the nuclear lamina, which mediated stiffness-dependent chromatin remodeling. By contrast, depletion of the cytolinker plectin had the opposite effect and promoted increased mechanoresponsiveness and up-regulation of lamin A/C. Together, these results demonstrate that the keratin cytoskeleton plays a key role in matrix rigidity sensing and downstream signal transduction.

The keratin network of intermediate filaments regulates keratinocyte rigidity sensing and nuclear mechanotransduction