Short Title: α-adducin modulates desmosomal turnover 2 ABBREVIATIONS: Add1 = α-adducin; AFM = atomic force microscope; BSA = bovine serum albumin; ctrl = control; Dsg = desmoglein; E-Cad = cadherin; FDC = force-distance curve; FRAP = fluorescent recovery after photobleaching; ko = knockout; MEK = murine keratinocyte; scFv = single chain variable fragment; wt = wildtype;
ORCIDs:ABSTRACT Intercellular adhesion is essential for tissue integrity and homeostasis. Desmosomes are especially abundant in the epidermis and the myocardium, tissues, which are under constantly changing mechanical stresses. Yet, it is largely unclear whether desmosomal adhesion can be rapidly adapted to changing demands and the mechanisms underlying desmosome turnover are only partially understood. We here show that loss of the actin-binding protein α-adducin prevented the ability of cultured keratinocytes or murine epidermis to withstand mechanical stress paralleled with reduced desmosome number. This effect was not caused by decreased levels or impaired adhesive properties of desmosomal molecules but rather by altered desmosome turnover. Mechanistically, reduced cortical actin density in α-adducin knockout keratinocytes resulted in increased mobility of the desmosomal adhesion molecule desmoglein 3 (Dsg3) and impaired interactions with Ecadherin, a crucial step in desmosome formation. Accordingly, loss of α-adducin prevented increased membrane localization of Dsg3 in response to cyclic stretch or shear stress. Our data demonstrate plasticity of desmosomal molecules in response to mechanical stimuli and unravel a mechanism how the actin cytoskeleton indirectly shapes intercellular adhesion by restricting the mobility of desmosomal molecules.