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Background  Recombinant human Fibroblast growth factor 21 (rhFGF21) is an endocrine hormone that has profound effects on treatment of metabolic diseases. However, rhFGF21 is prone to form inclusion body when expressed in bacteria, which results in, the downstream process of purification of bioactive rhFGF21 is time-consuming and labor intensive. The aim of this work is to explore a new method for improving the soluble expression and secretion level of rhFGF21 in  B. subtilis .    Results  A codon optimized rhFGF21 gene was expressed under the control of a strong inducible promoter P  malA   in  B. subtilis . A mini-cistron cassette (from  gsiB ) was located upstream of rhFGF21 in expression vector (pMATEFc5), which could reduce the locally stabilized mRNA secondary structure of transcripts and enhance the efficiency of translation initiation. Then various chaperones were further overexpressed to improve the expression efficiency of rhFGF21. Results showed that overexpression of the chaperone DnaK contributed to the increase of solubility of rhFGF21. Moreover, an extracellular proteases deficient strain  B. subtilis  Kno6cf was used to accumulate the secreted rhFGF21 solidly. In addition, eleven signal peptides from  B. subtilis  were evaluated and the SP  dacB   appeared the highest secretion yield of rhFGF21 in  B. subtilis . Finally, the combinatorial optimized strain achieved an about ninefold increase of the soluble rhFGF21 production after 24 h of flask fermentation in comparison with the initial production strain.    Conclusion  This work provided a comprehensive strategy for secretory expressing the heterologous protein rhFGF21 in  B. subtilis.  To our knowledge, this is the first report of the highly efficient production of rhFGF21 in  B. subtilis  and this approach may provide some suggestions for heterologous proteins production in  B. subtilis .    Electronic supplementary material  The online version of this article (10.1186/s12934-019-1066-4) contains supplementary material, which is available to authorized users.

microbial cell factories

High-efficiency expression and secretion of human FGF21 in Bacillus subtilis by intercalation of a mini-cistron cassette and combinatorial optimization of cell regulatory components