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MondoA Senses Non-glucose Sugars

C. Stoltzman,Mohan R. Kaadige,Christopher W. Peterson,D. Ayer

Published 2011 in Journal of Biological Chemistry

ABSTRACT

Background: Glucose is a fundamental metabolite that is sensed by the MondoA transcription complex. MondoA elevates transcription of thioredoxin-interacting protein to restrict glucose uptake. Results: MondoA senses the phosphorylated forms of the non-glucose hexose sugars, allose, and 3-O-methylglucose and triggers an adaptive transcriptional response. Conclusion: TXNIP is regulated by non-hexose sugars in a manner that requires their metabolism, and TXNIP is part of the hexose transport curb. Significance: Sugar is a universal metabolite, so how cells respond to changes in glucose and the transcriptional level is an important question. Glucose is required for cell growth and proliferation. The MondoA·Mlx transcription factor is glucose-responsive and accumulates in the nucleus by sensing glucose 6-phosphate. One direct and glucose-induced target of MondoA·Mlx complexes is thioredoxin-interacting protein (TXNIP). TXNIP is a potent negative regulator of glucose uptake, and hence its regulation by MondoA·Mlx triggers a feedback loop that restricts glucose uptake. This feedback loop is similar to the “hexose transport curb” first described almost 30 years ago. We show here that MondoA responds to the non-glucose hexoses, allose, 3-O-methylglucose, and glucosamine by accumulating in the nucleus and activating TXNIP transcription. The metabolic inhibitor 3-bromopyruvate blocks the transcriptional response to allose and 3-O-methylglucose, indicating that their metabolism, or a parallel pathway, is required to stimulate MondoA activity. Our dissection of the hexosamine biosynthetic pathway suggests that in addition to sensing glucose 6-phosphate, MondoA can also sense glucosamine 6-phosphate. Analysis of glucose uptake in wild-type, MondoA-null, or TXNIP-null murine embryonic fibroblasts indicates a role for the MondoA-TXNIP regulatory circuit in the hexose transport curb, although other redundant pathways also contribute.

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