Journal of Biological Chemistry
Volume 293, Issue 37, September 2018, Pages 14557-14568
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Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells

https://doi.org/10.1074/jbc.RA118.004169Get rights and content
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Cellular heme is thought to be distributed between a pool of sequestered heme that is tightly bound within hemeproteins and a labile heme pool required for signaling and transfer into proteins. A heme chaperone that can hold and allocate labile heme within cells has long been proposed but never been identified. Here, we show that the glycolytic protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) fulfills this role by acting as an essential repository and allocator of bioavailable heme to downstream protein targets. We identified a conserved histidine in GAPDH that is needed for its robust heme binding both in vitro and in mammalian cells. Substitution of this histidine, and the consequent decreases in GAPDH heme binding, antagonized heme delivery to both cytosolic and nuclear hemeprotein targets, including inducible nitric-oxide synthase (iNOS) in murine macrophages and the nuclear transcription factor Hap1 in yeast, even though this GAPDH variant caused cellular levels of labile heme to rise dramatically. We conclude that by virtue of its heme-binding property, GAPDH binds and chaperones labile heme to create a heme pool that is bioavailable to downstream proteins. Our finding solves a fundamental question in cell biology and provides a new foundation for exploring heme homeostasis in health and disease.

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This work was supported by National Institutes of Health Grants RO1 GM097041 (to D. J. S.), PO1 HL081064 Project 3 and PO1 HL103453 Project 3 (to D. J. S.), and R21 ES025661 (to A. R. R.), National Science Foundation Grant MCB-1552791 (to A. R. R.), an American Heart Association Postdoctoral Fellowship (to E. A. S.), the Blanchard Professorship (to A. R. R.), and Georgia Institute of Technology start-up funds (to A. R. R.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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1

Both authors contributed equally to this work.

2

Present address: Dept. of Physiology and Pharmacology, University of Toledo, Toledo, OH 43614.