Low cell tolerance is a basic issue in high-glucose fermentation under high temperature to economically obtain high product titer. Candida glycerinogenes, an industrial yeast, has excellent tolerance to the combined heat and high-glucose stress than Saccharomyces cerevisiae. The potential mechanism responsible for the high tolerance was illustrated here. The transcription of the potential stress-responsive genes in two strains were varied under single stress (heat or high glucose), especially the ribosome-related genes. Unlike S. cerevisiae, C. glycerinogenes up-regulated 17 genes, including most of the single stress responsive genes, and genes Avt1 and Pik1 under the combined stress, indicating a more systematic stress-responsive system in C. glycerinogenes. Further down-regulating the 17 potential key responsive genes indicated that genes DipS, Gpd1, PJk1, Hxt4, Hxt6, and Ino4 are important for cell tolerance to the combined stress. Furthermore, most of the ribosomal function related genes, such as Mrt4, Nug1, Nop53, Rpa190, Rex4, and Nsr1, play important role in cell tolerance. Therefore, the wider responsive gene spectrum and the activated expression of ribosomal function related genes might be key and prerequisite factors for the excellent tolerance to the combined stress of C. glycerinogenes. (C) 2018, The Society for Biotechnology, Japan. All rights reserved.