Nuclear mechanotransduction: sensing the force from within

- Despite lacking a direct extracellular attachment, the cell nucleus is a potent mechanotransducer.
- The A-type nuclear lamina scales with extracellular stiffness and contributes to nucleus mechanics.
- The conversion into biochemical outputs is mediated via protein forced unfolding, filament pulling and chromatin stretching.
- Mechanotransduced signals propagate via conserved pathways to regulate gene expression and direct cell fate.
- Applied tension across the extracellular matrix, the cytoskeleton and the nuclear lamina stabilizes a contractile cell state.

The cell nucleus is a hallmark of eukaryotic evolution, where gene expression is regulated and the genome is replicated and repaired. Yet, in addition to complex molecular processes, the nucleus has also evolved to serve physical tasks that utilize its optical and mechanical properties. Nuclear mechanotransduction of externally applied forces and extracellular stiffness is facilitated by the physical connectivity of the extracellular environment, the cytoskeleton and the nucleoskeletal matrix of lamins and chromatin. Nuclear mechanosensor elements convert applied tension into biochemical cues that activate downstream signal transduction pathways. Mechanoregulatory networks stabilize a contractile cell state with feedback to matrix, cell adhesions and cytoskeletal elements. Recent advances have thus provided mechanistic insights into how forces are sensed from within, that is, in the nucleus where cell-fate decision-making is performed.