Abstract
Aspergilli have been widely used in the production of organic acids, enzymes, and secondary metabolites for almost a century. Today, several GRAS (generally recognized as safe) Aspergillus species hold a central role in the field of industrial biotechnology with multiple profitable applications. Since the 1990s, research has focused on the use of Aspergillus species in the development of cell factories for the production of recombinant proteins mainly due to their natively high secretion capacity. Advances in the Aspergillus-specific molecular toolkit and combination of several engineering strategies (e.g., protease-deficient strains and fusions to carrier proteins) resulted in strains able to generate high titers of recombinant fungal proteins. However, the production of non-fungal proteins appears to still be inefficient due to bottlenecks in fungal expression and secretion machinery. After a brief overview of the different heterologous expression systems currently available, this review focuses on the filamentous fungi belonging to the genus Aspergillus and their use in recombinant protein production. We describe key steps in protein synthesis and secretion that may limit production efficiency in Aspergillus systems and present genetic engineering approaches and bioprocessing strategies that have been adopted in order to improve recombinant protein titers and expand the potential of Aspergilli as competitive production platforms.
Highlights
Proteins are functionally versatile biomolecules involved in multiple biological processes in the cell
We focus on the use of Aspergillus species in the manufacturing of recombinant proteins
An alternative practice to downstream in vitro treatment with proteases is to incorporate a protease cleavage site (e.g., Lys-Arg) between the native and the foreign protein, which can be proteolytically cleaved by fungal endoproteases (e.g., KEXB endoprotease in A. niger) during secretion [114,121,122]
Summary
Proteins are functionally versatile biomolecules (e.g., enzymes, structural proteins, and hormones) involved in multiple biological processes in the cell Despite their role in supporting biological systems, proteins have been extensively studied for their potential in the formulation of commercial products. The structure and function of the protein of interest determines which production system is the most appropriate to be used When it comes to manufacturing therapeutic proteins of high quality, mammalian cell lines are predominantly used, as they can produce complex, human-like glycosylated proteins that are safe for patients. Several reviews have described the potentials of filamentous fungi in the production of pharmaceutical and other industrial proteins, as well as the genetic engineering approaches followed to maximize production levels [7,16,17]. Bottlenecks in protein synthesis and secretion are discussed, while our comprehensive literature search provides a general overview of the most important genetic engineering projects and bioprocessing strategies applied over the past 30 years to improve recombinant protein yields in Aspergillus
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