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Background Kluyveromyces marxianus  is a promising cell factory for producing bioethanol and that raised a demand for a high yield of heterologous proteins in this species. Expressions of heterologous proteins usually lead to the accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER) and then cause ER stress. To cope with this problem, a group of ER stress response target genes (ESRTs) are induced, mainly through a signaling network called unfolded protein response (UPR). Characterization and modulation of ESRTs direct the optimization of heterologous expressions. However, ESRTs in  K. marxianus  have not been identified so far. Results In this study, we characterized the ER stress response in  K. marxianus  for the first time, by using two ER stress-inducing reagents, dithiothreitol (DTT) and tunicamycin (TM). Results showed that the Kar2–Ire1–Hac1 pathway of UPR is well conserved in  K. marxianus . About 15% and 6% of genes were upregulated during treatment of DTT and TM, respectively. A total of 115 upregulated genes were characterized as ESRTs, among which 97 genes were identified as UPR target genes and 37 UPR target genes contained UPR elements in their promoters. Genes related to carbohydrate metabolic process and actin filament organization were identified as new types of UPR target genes. A total of 102 ESRTs were overexpressed separately in plasmids and their effects on productions of two different lignocellulolytic enzymes were systematically evaluated. Overexpressing genes involved in carbohydrate metabolism, including  PDC1 ,  PGK  and  VID28 , overexpressing a chaperone gene  CAJ1  or overexpressing a reductase gene  MET13  substantially improved secretion expressions of heterologous proteins. Meanwhile, overexpressing a novel gene,  KLMA_50479  (named  ESR1 ), as well as overexpressing genes involved in ER-associated protein degradation (ERAD), including  HRD3 ,  USA1  and YET3 , reduced the secretory expressions.  ESR1  and the aforementioned ERAD genes were deleted from the genome. Resultant mutants, except the  yet3 Δ mutant, substantially improved secretions of three different heterologous proteins. During the fed-batch fermentation, extracellular activities of an endoxylanase and a glucanase in  hrd3 Δ cells improved by 43% and 28%, respectively, compared to those in wild-type cells. Conclusions Our results unveil the transcriptional scope of the ER stress response in  K. marxianus  and suggest efficient ways to improve productions of heterologous proteins by manipulating expressions of ESRTs.

biotechnology for biofuels

Characterization and modulation of endoplasmic reticulum stress response target genes in Kluyveromyces marxianus to improve secretory expressions of heterologous proteins