Human CHAC1 Protein Degrades Glutathione, and mRNA Induction Is Regulated by the Transcription Factors ATF4 and ATF3 and a Bipartite ATF/CRE Regulatory Element

Crawford, Rebecca; Prescott, Eugenia T; Sylvester, Charity F.; Higdon, Ashlee N.; Shan, Jixiu; Kilberg, Michael S.; Mungrue, Imran N.

doi:10.1074/jbc.m114.635144

Cited by 172 publications

(165 citation statements)

References 45 publications

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“…Recently, Chac1 was reported to function as a γ-glutamyl cyclo-transferase (GGCT) that catalyzes conversion of glutathione (GSH), a tripeptide thiol antioxidant (γ-Glu-Cys-Gly), to 5-oxyProline and Cys-Gly (49, 50). Since Chac1 was highly up-regulated in Lop/+ lenses we predicted that GSH levels may be depleted as a consequence of GGCT activity.…”

Section: Resultsmentioning

confidence: 99%

Lens ER-stress response during cataract development in Mip-mutant mice

Zhou

Bennett

Shiels

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Major intrinsic protein (MIP) is a functional water-channel (AQP0) that also plays a key role in establishing lens fiber cell architecture. Genetic variants of MIP have been associated with inherited and age-related forms of cataract; however, the underlying pathogenic mechanisms are unclear. Here we have used lens transcriptome profiling by microarray-hybridization and qPCR to identify pathogenic changes during cataract development in Mip-mutant (Lop/+) mice. In postnatal Lop/+ lenses (P7) 99 genes were up-regulated and 75 were down-regulated (>2-fold, p=<0.05) when compared with wild-type. A pathway analysis of up-regulated genes in the Lop/+ lens (P7) was consistent with endoplasmic reticulum (ER)-stress and activation of the unfolded protein response (UPR). The most up-regulated UPR genes (>4-fold) in the Lop/+ lens included Chac1 > Ddit3 > Atf3 > Trib3 > Xbp1 and the most down-regulated genes (>5-fold) included two anti-oxidant genes, Hspb1 and Hmox1. Lop/+ lenses were further characterized by abundant TUNEL-positive nuclei within central degenerating fiber cells, glutathione depletion, free-radical overproduction, and calpain hyper-activation. These data suggest that Lop/+ lenses undergo proteotoxic ER-stress induced cell-death resulting from prolonged activation of the Eif2ak3/Perk-Atf4-Ddit3-Chac1 branch of the UPR coupled with severe oxidative-stress.

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Section: Resultsmentioning

confidence: 99%

Lens ER-stress response during cataract development in Mip-mutant mice

Zhou

Bennett

Shiels

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Kumar et al showed the overexpression of CHAC1-caused GSH depletion in mammalian cells [41]. Crawford et al revealed that overexpression of CHAC1 led to a large decrease in total GSH, which was alleviated in a CHAC1 catalytic mutant in HEK293 cells [42]. Therefore, CHAC1 expression is associated with GSH metabolism; CHAC1 plays a critically important role in the process of melanogenesis.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Profile Analysis of Mechanisms of Black and White Plumage Determination in Black-Bone Chicken

Wang

Liao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Melanin is a major and ubiquitous component of plumage colouration, and patterns of melanin pigmentation in birds are extremely varied. However, the molecular mechanism of pigmentation in avian plumage is still largely unknown. Methods: To elucidate the molecular mechanisms involved in the formation of black and white plumage, this study takes advantage of high-throughput sequencing technology to compare differences in the transcriptome between black and white chicken feather bulbs. In total, we constructed six cDNA libraries from black (Group B) and white (Group W) feather bulbs in the dorsal plumage of Muchuan black-boned chickens. Results: A comparison between Groups B and W revealed 61 differentially expressed genes, with 47 displaying higher, and 14 displaying lower, levels of expression in white feather bulbs. Our results revealed a set of candidate genes and two potential metabolic pathways involved in black-bone chicken plumage melanogenesis. These include four homeobox genes (HOXB9, HOXC8, HOXA9, and HOXC 9), two glutathione (GSH) metabolism-related genes (CHAC1 and GPX3), and the transforming growth factor beta (TGF-β) signalling pathway. Two known genes, TYR and MITF, were also shown to play a role in melanin formation. Conclusion: our data provide a valuable resource for discovering genes important in plumage melanin formation and will help further elucidate the molecular mechanisms for black and white plumage.

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“…However, in the higher multicellular eukaryotes, two ChaC homologues are present, ChaC1 and ChaC2. Although the mouse and human ChaC1 function as glutathione-degrading enzymes (10,19), the function of the mammalian ChaC2 proteins has not been explored.…”

mentioning

confidence: 99%

ChaC2, an Enzyme for Slow Turnover of Cytosolic Glutathione

Kaur

Gautam

Srivastava

et al. 2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeGlutathione degradation plays an important role in glutathione and redox homeostasis, and thus it is imperative to understand the enzymes and the mechanisms involved in glutathione degradation in detail. We describe here ChaC2, a member of the ChaC family of ␥-glutamylcyclotransferases, as an enzyme that degrades glutathione in the cytosol of mammalian cells. ChaC2 is distinct from the previously described ChaC1, to which ChaC2 shows ϳ50% sequence identity. and ChaC2 proteins also shared the same specificity for reduced glutathione, with no activity against either ␥-glutamyl amino acids or oxidized glutathione. The ChaC2 proteins were found to be expressed constitutively in cells, unlike the tightly regulated ChaC1. Moreover, lower eukaryotes have a single member of the ChaC family that appears to be orthologous to ChaC2. In addition, we determined the crystal structure of yeast ChaC2 homologue, GCG1, at 1.34 Å resolution, which represents the first structure of the ChaC family of proteins. The catalytic site is defined by a fortuitous benzoic acid molecule bound to the crystal structure. The mechanism for binding and catalytic activity of this new enzyme of glutathione degradation, which is involved in continuous but basal turnover of cytosolic glutathione, is proposed.

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Human CHAC1 Protein Degrades Glutathione, and mRNA Induction Is Regulated by the Transcription Factors ATF4 and ATF3 and a Bipartite ATF/CRE Regulatory Element

Cited by 172 publications

References 45 publications

Lens ER-stress response during cataract development in Mip-mutant mice

Lens ER-stress response during cataract development in Mip-mutant mice

Transcriptome Profile Analysis of Mechanisms of Black and White Plumage Determination in Black-Bone Chicken

ChaC2, an Enzyme for Slow Turnover of Cytosolic Glutathione

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