The invention is directed to methods of producing a polypeptide or a variant thereof, wherein the polypeptide or variant thereof is dependent on LIMP-2 for trafficking, localization, stabilization and/or sorting of the polypeptide in the cell. In general, the methods comprise culturing a lysosomal integral membrane protein II (LIMP-2) deficient cell which expresses the polypeptide or the variant thereof under conditions in which the polypeptide or the variant thereof is produced.