title: Fission yeast Ubr1 ubiquitin ligase influences the oxidative stress response via degradation of active Pap1 bZIP transcription factor in the nucleus.
abstract: Cells adapt to oxidative stress by transcriptional activation of genes encoding antioxidants and proteins of other protective roles. A bZIP transcription factor, Pap1, plays a critical role in this process and overexpression of Pap1 confers resistance to various oxidants and drugs in fission yeast. Pap1 temporarily enters the nucleus upon oxidative stress but returns to the cytoplasm once cells adapt to the stress, suggesting that cellular localization regulates Pap1 function. We report here an additional regulatory mechanism that Ubr1 ubiquitin ligase-dependent degradation lowered the Pap1 protein levels. ubr1 cells were causally resistant to hydrogen peroxide because of the increment of Pap1 levels. Pap1 was preferentially degraded in the nucleus where Ubr1 was consistently enriched. Proteolysis was critical to downregulate Pap1 especially when its activation persisted, as constitutively nuclear Pap1 severely inhibited growth in ubr1 mutants. Inactive mutations in the bZIP DNA binding domain stabilized Pap1 but rescued the lethality caused by constitutively active Pap1 in ubr1 mutants. These findings indicate that either nuclear export or Ubr1-mediated proteolysis must be operative to prevent uncontrolled Pap1 function. Coincidental dysfunction in both inhibitory pathways causes lethality because of prolonged activation of Pap1. Ubr1 is a critical regulator for the homeostasis of oxidative stress response.
authors.affiliation: Center for Gene Science, Hiroshima University, Kagamiyama 1-4-2, Higashi-Hiroshima 739-8527, Japan. kkita@hiroshima-u.ac.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitamura
authors.forename: Masumi
authors.initials: M
authors.lastname: Taki
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Tanaka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yamashita
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006861:Hydrogen Peroxide / Q000633:toxicity; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D000073718:Pancreatitis-Associated Proteins; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000502:physiology*; D013312:Stress, Physiological
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D005656:Fungal Proteins; D050505:Mutant Proteins; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D006861:Hydrogen Peroxide