Assembly with the Na,K-ATPase α1 Subunit Is Required for Export of β1 and β2 Subunits from the Endoplasmic Reticulum

Abstract

The level of the heterodimeric Na,K-ATPase is tightly controlled in epithelia to maintain appropriate transport function. The catalytic Na,K-ATPase α subunit is not able to exit the ER or catalyze ion transport unless assembled with the β subunit. However, requirements for the ER exit of the Na,K-ATPase β subunit that plays an additional, ion-transport-independent, role in intercellular adhesion are not clear. Exogenous β₁ or β₂ subunits expressed in renal MDCK cells replace endogenous β₁ subunits in the α−β complexes in the ER, resulting in a decrease in the amount of the α₁-bound endogenous β₁ subunits by 47−61% with no change in the amount of α₁ subunits. Disruption of the α₁−β association by mutations in defined α₁-interacting regions of either β₁ or β₂ subunits results in the ER retention and rapid degradation of unassembled mutants. Hence, the ER quality control system allows export only of assembled α−β complexes to the Golgi, thereby maintaining an equimolar ratio of α and β subunits in the plasma membrane, whereas the number of α₁ subunits in the ER determines the amount of the α−β complexes.