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Pathway engineering facilitates efficient protein expression in Pichia pastoris

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Pichia pastoris has been recognized as an important platform for the production of various heterologous proteins in recent years. The strong promoter AOX1, induced by methanol, with the help of the α-pre-pro signal sequence, can lead to a high expression level of extracellular protein. However, this combination was not always efficient, as protein secretion in P. pastoris involves numerous procedures mediated by several cellular proteins, including folding assisted by endoplasmic reticulum (ER) molecular chaperones, degradation through ubiquitination, and an efficient vesicular transport system. Efficient protein expression requires the cooperation of various intracellular pathways. This article summarizes the process of protein secretion, modification, and transportation in P. pastoris. In addition, the roles played by the key proteins in these processes and the corresponding co-expression effects are also listed. It is expected to lay the foundation for the industrial protein production of P. pastoris.

Key points

Mechanisms of chaperones in protein folding and their co-expression effects are summarized.

Protein glycosylation modifications are comprehensively reviewed.

Current dilemmas in the overall protein secretion pathway of Pichia pastoris and corresponding solutions are demonstrated.

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This work was financially supported by the National Key Research and Development Program of China (No. 2021YFC2100900), the National Natural Science Foundation of China (No. 21978116 and 32171261), and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. KYCX22_2439).

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JG and JS conceived of and designed the article. CS, Hui Li, Heng Li, and ZR analyzed the data. ZX performed the research. CL wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jin-Song Gong or Jin-Song Shi.

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Liu, C., Gong, JS., Su, C. et al. Pathway engineering facilitates efficient protein expression in Pichia pastoris. Appl Microbiol Biotechnol 106, 5893–5912 (2022).

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