A cellular UDP-glucose deficiency causes overexpression of glucose/oxygen-regulated proteins independent of the endoplasmic reticulum stress elements

A low level of UDP- Glc occurs in cells exposed to hypoxia or glucose starvation. This work reveals that a 65% reduction in the cellular UDP- Glc level causes upregulation of the mitochondrial chaperone GRP75 and the endoplasmic reticulum ( ER) resident chaperones GRP58, ERp72, GRP78, GRP94, GRP170, and calreticulin. Conditions that cause misfolding of proteins within the ER activate the transcription factors ATF6alpha/beta and induce translation of the transcription factors XBP- 1/ TREB5 and ATF4/ CREB2. These transcription factors induce the overexpression of ER chaperones and CHOP/ GADD153. However, the 65% decrease in the cellular UDP- Glc level does not cause activation of ATF6alpha, splicing of XBP- 1/ TREB5, induction of ATF4/ CREB2, or expression of CHOP/ GADD153. The activity of the promoters of the ER chaperones is increased in UDP- Glc-deficient cells, but the activity of the CHOP/ GADD153 promoter is not affected, in comparison with their respective activities in cells having compensated for the UDP- Glc deficiency. The results demonstrate that the unfolded protein response remains functionally intact in cells with a 65% decrease in the cellular UDP- Glc level and provide evidence that this decrease is a stress signal in mammalian cells, which triggers the coordinate overexpression of mitochondrial and ER chaperones, independently of the ER stress elements.