Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease

Iron has played an important role in energy production since the beginning of life, as iron-catalyzed redox reactions are required for energy production. Oxygen, a highly efficient electron acceptor with high reduction potential, facilitates highly efficient energy production in eukaryotic cells. However, the increasing atmospheric oxygen concentration produces new threats to the organism, as oxygen reacts with iron and produces reactive oxygen species unless its levels are strictly regulated. As the size of multicellular organisms increases, these organisms must transport oxygen to the peripheral tissues and begin to employ red blood cells containing hemoglobin. This system is potentially a double-edged sword, as hemoglobin autoxidation occurs at a certain speed and releases free iron into the cytoplasm. Nrf2 belongs to the CNC transcription factor family, in which NF-E2p45 is the founding member. NF-E2p45 was first identified as a transcription factor that binds to the erythroid gene regulatory element NF-E2 located in the promoter region of the heme biosynthetic porphobilinogen deaminase gene. Human Nrf2 was also identified as a transcription factor that binds to the regulatory region of the β-globin gene. Despite these original findings, NF-E2p45 and Nrf2 knockout mice exhibit few erythroid phenotypes. Nrf2 regulates the expression of a wide range of antioxidant and detoxification enzymes. In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen

Ribosome binding protein GCN1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice.

Amino acids exert many biological functions, serving as allosteric regulators and neurotransmitters, as constituents in proteins and as nutrients. GCN2-mediated phosphorylation of eukaryotic initiation factor 2 alpha (elF2α) restores homeostasis in response to amino acid starvation (AAS) through the inhibition of the general translation and upregulation of amino acid biosynthetic enzymes and transporters by activating the translation of Gcn4 and ATF4 in yeast and mammals, respectively. GCN1 is a GCN2-binding protein that possesses an RWD binding domain (RWDBD) in its C-terminus. In yeast, Gcn1 is essential for Gcn2 activation by AAS; however, the roles of GCN1 in mammals need to be established. Here, we revealed a novel role of GCN1 that does not depend on AAS by generating two Gcn1 mutant mouse lines: Gcn1-knockout mice (Gcn1 KO mice (Gcn1-/-)) and RWDBD-deleted mutant mice (Gcn1ΔRWDBD mice). Both mutant mice showed growth retardation, which was not observed in the Gcn2 KO mice, such that the Gcn1 KO mice died at the intermediate stage of embryonic development because of severe growth retardation, while the Gcn1ΔRWDBD embryos showed mild growth retardation and died soon after birth, most likely due to respiratory failure. Extension of pregnancy by 24 h through the administration of progesterone to the pregnant mothers rescued the expression of differentiation markers in the lungs and prevented lethality of the Gcn1ΔRWDBD pups, indicating that perinatal lethality of the Gcn1ΔRWDBD embryos was due to simple growth retardation. Similar to the yeast Gcn2/Gcn1 system, AAS- or UV irradiation-induced elF2α phosphorylation was diminished in the Gcn1ΔRWDBD mouse embryonic fibroblasts (MEFs), suggesting that GCN1 RWDBD is responsible for GCN2 activity. In addition, we found reduced cell proliferation and G2/M arrest accompanying a decrease in Cdk1 and Cyclin B1 in the Gcn1ΔRWDBD MEFs. Our results demonstrated, for the first time, that GCN1 is essential for both GCN2-dependent stress response and GCN2-independent cell cycle regulation

Lipocalin function of E.coli zinT (yodA) protein.

重金属やアミトロール(AT)で発現誘導され、大腸菌ストレス応答タンパク質の一種であるzinT (yodA)は、一次構造比較やX線結晶構造解析による三次元立体構造などから、C末端領域に金属結合部位を持つこと、ABC transporter やlipocalinファミリーと一部相同なアミノ酸配列を持つことが明らかとなっているが、zinTの金属以外の低分子結合能については報告がない。そこで本研究では、大腸菌zinTタンパク質の種々の物質との結合能を、野生型zinTおよびN末端22残基欠損体(ΔN22)を用いて検討した。 まず、zinTの分子内TyrまたはTrp蛍光を指標として、種々の物質を添加に伴う蛍光強度の減少を測定した。低分子化合物としては、(1)ATおよびdNTP(2) 脂肪酸および脂質5種、(3) 複素式化合物3種、(4)芳香族化合物3種を検討し、zinTに対しそれぞれ添加し、30℃、10分間保温後、蛍光スペクトルを測定した。その結果、化合物添加によりzinTの最大蛍光強度は濃度依存的に減少し、特にdNTP, Qurcetinおよび8-ANSで顕著に見られた。また、野生型とΔN22において、蛍光減少の濃度依存性に顕著な差異は見られなかった。以上より、zinTは疎水性低分子化合物結合能(lipocalin活性)を有し、N末端領域のlipocalin活性に対する寄与は少ないことが明らかとなった

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae. VIII: The Eighth Year (2015-2016)

Continuing the project described by Kato et al. (2009, arXiv:0905.1757), we collected times of superhump maxima for 128 SU UMa-type dwarf novae observed mainly during the 2015-2016 season and characterized these objects. The data have improved the distribution of orbital periods, the relation between the orbital period and the variation of superhumps, the relation between period variations and the rebrightening type in WZ Sge-type objects. Coupled with new measurements of mass ratios using growing stages of superhumps, we now have a clearer and statistically greatly improved evolutionary path near the terminal stage of evolution of cataclysmic variables. Three objects (V452 Cas, KK Tel, ASASSN-15cl) appear to have slowly growing superhumps, which is proposed to reflect the slow growth of the 3:1 resonance near the stability border. ASASSN-15sl, ASASSN-15ux, SDSS J074859.55+312512.6 and CRTS J200331.3-284941 are newly identified eclipsing SU UMa-type (or WZ Sge-type) dwarf novae. ASASSN-15cy has a short (~0.050 d) superhump period and appears to belong to EI Psc-type objects with compact secondaries having an evolved core. ASASSN-15gn, ASASSN-15hn, ASASSN-15kh and ASASSN-16bu are candidate period bouncers with superhump periods longer than 0.06 d. We have newly obtained superhump periods for 79 objects and 13 orbital periods, including periods from early superhumps. In order that the future observations will be more astrophysically beneficial and rewarding to observers, we propose guidelines how to organize observations of various superoutbursts.Comment: 123 pages, 162 figures, 119 tables, accepted for publication in PASJ (including supplementary information

First detection of two superoutbursts during rebrightening phase of a WZ Sge-type Dwarf Nova : TCP J21040470+4631129

We report on photometric and spectroscopic observations and analysis of the 2019 superoutburst of TCP J21040470+4631129. This object showed a 9 mag superoutburst with early superhumps and ordinary superhumps, which are the features of WZ Sge-type dwarf novae. Five rebrightenings were observed after the main superoutburst. The spectra during the post-superoutburst stage showed Balmer, He I, and possible sodium doublet features. The mass ratio is derived as 0.0880(9) from the period of the superhump. During the third and fifth rebrightenings, growing superhumps and superoutbursts were observed, which have never been detected during a rebrightening phase among WZ Sge-type dwarf novae with multiple rebrightenings. To induce a superoutburst during the brightening phase, the accretion disk needs to have expanded beyond the 3 : 1 resonance radius of the system again after the main superoutburst. These peculiar phenomena can be explained by the enhanced viscosity and large radius of the accretion disk suggested by the higher luminosity and the presence of late-stage superhumps during the post-superoutburst stage, plus by more mass supply from the cool mass reservoir and/or from the secondary because of the enhanced mass transfer than those of other WZ Sge-type dwarf novae.peer-reviewe

First Detection of Two Superoutbursts during Rebrightening Phase of a WZ Sge-type Dwarf Nova: TCP J21040470+4631129

We report photometric and spectroscopic observations and analysis of the 2019 superoutburst of TCP J21040470+4631129. This object showed a 9-mag superoutburst with early superhumps and ordinary superhumps, which are the features of WZ Sge-type dwarf novae. Five rebrightenings were observed after the main superoutburst. The spectra during the post-superoutburst stage showed the Balmer, He I and possible sodium doublet features. The mass ratio is derived as 0.0880(9) from the period of the superhump. During the third and fifth rebrightenings, growing superhumps and superoutbursts were observed, which have never been detected during a rebrightening phase among WZ Sge-type dwarf novae with multiple rebrightenings. To induce a superoutburst during the brightening phase, the accretion disk was needed to expand beyond the 3:1 resonance radius of the system again after the main superoutburst. These peculiar phenomena can be explained by the enhanced viscosity and large radius of the disk suggested by the higher luminosity and the presence of late-stage superhumps during the post-superoutburst stage, plus by more mass supply from the cool mass reservoir and/or from the secondary because of the enhanced mass transfer than those of other WZ Sge-type dwarf novae.Comment: 13 pages, 10 figures, accepted for publication in PAS