Thus, our results are fully consistent with a role for mammalian CNIH-2 as an ER cargo exporter: it could take up cargo proteins within the ER, mediate their preferential export by interacting with the COPII coat, then might release their cargo in the Golgi complex and finally cycle back to the ER to take up new cargo. Additional evidence for the hypothesis that mammalian CNIH-2 increases the surface density of GluA receptors by facilitating their ER export is provided by the observation that CNIH-2 co-expression did not only increase the amount of GluA on the cell surface but also in total cell lysates. Protein homeostasis in the ER can be modeled as a balance between three interacting pathways: ER-assisted protein folding, export of proteins from the ER and their ER-associated degradation [46]. Thus, if ER export of GluA is enhanced by CNIH-2, its ER-associated degradation will be less engaged explaining the reported increase in total amount of GluA protein. Finally, we could exclude the retrograde transport of GluA subunits being affected by CNIH-2, as dominant-negative inhibition of clathrin-dependent endocytosis of GluA did not preclude the increase in surface expression by CNIH-2 co-expression.
