Basic leucine zipper transcription activators – tools to improve production and quality of human erythropoietin in Nicotiana benthamiana

Abstract Human erythropoietin (hEPO) is one of the most in‐demand biopharmaceuticals, however, its production is challenging. When produced in a plant expression system, hEPO results in extensive plant tissue damage and low expression. It is demonstrated that the modulation of the plant protein synthesis machinery enhances hEPO production. Co‐expression of basic leucine zipper transcription factors with hEPO prevents plant tissue damage, boosts expression, and increases hEPO solubility. bZIP28 co‐expression up‐regulates genes associated with the unfolded protein response, indicating that the plant tissue damage caused by hEPO expression is due to the native protein folding machinery being overwhelmed and that this can be overcome by co‐expressing bZIP28.