The nucleus forms a dynamic contact with the plasma membrane to maintain the glandular epithelial architecture

Abstract The maintenance of epithelial architecture relies on precise mechanical and biochemical cues. Recent studies reveal an unexpected role for the nucleus in maintaining epithelial architecture, but how the nucleus is physically and molecularly integrated into epithelia remains unclear. Here, we identify a dynamic basal actin spot that links the nucleus to plasma membrane β1-integrin through the linker of nucleoskeleton and cytoskeleton (LINC) in 3D breast acini. Depletion of LINC complex nesprin-2G, SUNs or FHOD1 disrupts nuclear positioning and inhibits lumen formation. Activation of a nesprin-2 degron causes acute loss of the basal actin spot and collapse of acini. Active Src and β1-integrin accumulate in the basal actin spot and Src activity is required to prevent collapse of acinar structure. These findings reveal an unexpected mode of nuclear-plasma membrane contact that we propose homeostatically regulates intracellular contractility through a Src signaling pathway to maintain global epithelial architecture. Competing Interest Statement The authors have declared no competing interest.