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 up-regulation 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.
Flores-Diaz
Marietta
M
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Higuita
Juan-Carlos
JC
Florin
Inger
I
Okada
Tetsuya
T
Pollesello
Piero
P
Bergman
Tomas
T
Thelestam
Monica
M
Mori
Kazutoshi
K
Alape-Giron
Alberto
A
D051702:Activating Transcription Factor 6; D000255:Adenosine Triphosphate / Q000737:chemistry; D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D037282:Calreticulin / Q000096:biosynthesis; D002352:Carrier Proteins / Q000096:biosynthesis; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005347:Fibroblasts / Q000378:metabolism; D005799:Genes, Dominant; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D000860:Hypoxia; D007535:Isomerases / Q000096:biosynthesis; D008156:Luciferases / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008565:Membrane Proteins / Q000096:biosynthesis; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000096:biosynthesis; D009154:Mutation; D010100:Oxygen / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D015854:Up-Regulation; D014532:Uridine Diphosphate Glucose / Q000172:deficiency*
D051702:Activating Transcription Factor 6; D022762:CCAAT-Enhancer-Binding Proteins; D037282:Calreticulin; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006023:Glycoproteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D014157:Transcription Factors; C062477:endoplasmic reticulum glycoprotein p72; C098410:glucose-regulated protein 170; C018551:glucose-regulated proteins; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D000255:Adenosine Triphosphate; D008156:Luciferases; D007535:Isomerases; D005947:Glucose; D010100:Oxygen; D014532:Uridine Diphosphate Glucose