The invention relates to systems and methods for producing proteins of interest. The invention employs genetically-engineered animal or plant cells that have modified protein folding or processing capacities. In one aspect, the invention features genetically-engineered cells comprising one or more recombinant expression cassettes which encode (1) a protein of interest and (2) a polypeptide that is functional in the unfolded protein response (UPR) pathway of the cells. Co-expression of the polypeptide significantly increases the yield of the protein of interest in the genetically-engineered cells. In one example, the genetically-engineered cells are animal cells, and the co-expressed polypeptide is a component or modulator of an XBP1- or ATF6-mediated UPR pathway.