title: Nicotinamide mononucleotide adenylyltransferase is a stress response protein regulated by the heat shock factor/hypoxia-inducible factor 1alpha pathway.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Yousuf O
authors.initials: YO
authors.lastname: Ali
authors.forename: Ryan
authors.initials: R
authors.lastname: McCormack
authors.forename: Andrew
authors.initials: A
authors.lastname: Darr
authors.forename: R Grace
authors.initials: RG
authors.lastname: Zhai
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000502:physiology*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D000076249:Heat Shock Transcription Factors; C053134:Hsf protein, Drosophila; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D009612:Nicotinamide-Nucleotide Adenylyltransferase