Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription.
Methylglyoxal is a highly reactive dicarbonyl degradation product formed from triose phosphates during glycolysis. Methylglyoxal forms stable adducts primarily with arginine residues of intracellular proteins. The biologic role of this covalent modification in regulating cell function is not known. Here, we report that in retinal Müller cells, increased glycolytic flux causes increased methylglyoxal modification of the corepressor mSin3A. Methylglyoxal modification of mSin3A results in increased recruitment of O-GlcNAc transferase to an mSin3A-Sp3 complex, with consequent increased modification of Sp3 by O-linked N-acetylglucosamine. This modification of Sp3 causes decreased binding of the repressor complex to a glucose-responsive GC box in the angiopoietin-2 promoter, resulting in increased Ang-2 expression. A similar mechanism involving methylglyoxal-modification of other coregulator proteins may play a role in the pathobiology of a variety of conditions associated with changes in methylglyoxal concentration, including cancer and diabetic vascular disease.
Yao
Dachun
D
JDRF International Center for Diabetic Complications Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Taguchi
Tetsuya
T
Matsumura
Takeshi
T
Pestell
Richard
R
Edelstein
Diane
D
Giardino
Ida
I
Suske
Guntram
G
Ahmed
Naila
N
Thornalley
Paul J
PJ
Sarthy
Vijay P
VP
Hammes
Hans-Peter
HP
Brownlee
Michael
M
D000595:Amino Acid Sequence; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011765:Pyruvaldehyde / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation; D015854:Up-Regulation
D042702:Angiopoietin-2; D012333:RNA, Messenger; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D011765:Pyruvaldehyde; D056264:Sin3 Histone Deacetylase and Corepressor Complex