Nicotinamide Mononucleotide Adenylyltransferase Is a Stress Response Protein Regulated by the Heat Shock Factor/Hypoxia-inducible Factor 1 Pathway

Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2011; 286(21):19089-99. DOI: 10.1074/jbc.M111.219295
Source: PubMed


Stress responses are cellular processes essential for maintenance of cellular integrity and defense against environmental and intracellular insults. Neurodegenerative conditions are linked with inadequate stress responses. Several stress-responsive genes encoding neuroprotective proteins have been identified, and among them, the heat shock proteins comprise an important group of molecular chaperones that have neuroprotective functions. However, evidence for other critical stress-responsive genes is lacking. Recent studies on the NAD synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT) have uncovered a novel neuronal maintenance and protective function against activity-, injury-, or misfolded protein-induced degeneration in Drosophila and in mammalian neurons. Here, we show that NMNAT is also a novel stress response protein required for thermotolerance and mitigation of oxidative stress-induced shortened lifespan. NMNAT is transcriptionally regulated during various stress conditions including heat shock and hypoxia through heat shock factor (HSF) and hypoxia-inducible factor 1α in vivo. HSF binds to nmnat promoter and induces NMNAT expression under heat shock. In contrast, under hypoxia, HIF1α up-regulates NMNAT indirectly through the induction of HSF. Our studies provide an in vivo mechanism for transcriptional regulation of NMNAT under stress and establish an essential role for this neuroprotective factor in cellular stress response.

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    • "Recent findings demonstrate that Drosophila NMNAT behaves as a chaperone protein and can be induced by heat shock [25], [26]. To investigate whether human NMNATs are inducible proteins, we then studied the effect of heat shock on their transcripts. "
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    ABSTRACT: Among the enzymes involved in NAD homeostasis, nicotinamide mononucleotide adenylyltransferases (NMNAT1-3) are central to intracellular NAD formation. Although NMNAT3 is postulated to be a mitochondrial enzyme contributing to NAD-dependent organelle functioning, information on endogenous proteins is lacking. We report that in human cells a single gene nmnat3 localized on chromosome 3 codes for two mRNA splice variants NMNATv1 and FKSG76, whereas the previously reported NMNAT3v2 transcript is not present. However, NMNAT3v1 and FKSG76 proteins are not detectable, consistent with the finding that an upstream ORF in their mRNAs negatively regulates translation. NMNAT3v1 transfection demonstrates that the protein is cytosolic and inactive, whereas FKSG76 is mitochondrial but operates NAD cleavage rather than synthesis. In keeping with the lack of NMNAT3, we show that extracellular NAD, but not its metabolic precursors, sustains mitochondrial NAD pool in an ATP-independent manner. Data of the present study modify the scenario of the origin of mitochondrial NAD by showing that, in human cells, NMNAT3 is absent in mitochondria, and, akin to plants and yeast, cytosolic NAD maintains the mitochondrial NAD pool.
    PLoS ONE 12/2013; 8(10):e76938. DOI:10.1371/journal.pone.0076938 · 3.23 Impact Factor
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    • "Indeed, structural studies of various Nmnats have revealed characteristic similarities to known chaperones such as UspA and Hsp100 [51]. Consistent with this notion, dNmnat was recently shown to function as a stress protein in response to heat shock, hypoxia, and the mitochondrial Complex I toxin, paraquat [52]. However, in dopaminergic neurons, Nmnat1 does not seem to function as either an axonal protectant or a chaperone. "
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