The filamentous fungus Aspergillus oryzae, which has long been used for the production of Japanese traditional fermented foods, has been attracting attention as a promising host for recombinant protein production because of its safety and a high capacity for protein secretion. The production levels in A. oryzae of most nonfungal proteins of higher eukaryote origin are generally low compared to those of homologous or other fungal proteins. The reduced yields of heterologous proteins are also a common problem in other filamentous fungal species. Thus, there have been many attempts to improve the production yield of heterologous proteins, particularly those derived from higher eukaryotes. Consequently, several trials have successfully resulted in an increase in the production level of recombinant proteins. This review focuses on the various strategies for improving heterologous protein production in A. oryzae, mainly for improving transcription and translation efficiencies, mRNA stability, and protein secretion, as well as for preventing proteolytic degradation. Although these strategies are individually effective in improvement of protein yields, combination of these methods should be required to achieve the commercial production levels of heterologous proteins from A. oryzae. In addition to the efforts in productivity improvement from the molecular aspects, application of the solid-state fermentation process would be advantageous for heterologous protein production by A. oryzae.
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