@article{3f5321e8a86643609dc589dcb07a2af9,
title = "The evolutionarily conserved arginyltransferase 1 mediates a pVHL-independent oxygen-sensing pathway in mammalian cells",
abstract = "The response to oxygen availability is a fundamental process concerning metabolism and survival/death in all mitochondria-containing eukaryotes. However, the known oxygen-sensing mechanism in mammalian cells depends on pVHL, which is only found among metazoans but not in other species. Here, we present an alternative oxygen-sensing pathway regulated by ATE1, an enzyme ubiquitously conserved in eukaryotes that influences protein degradation by posttranslational arginylation. We report that ATE1 centrally controls the hypoxic response and glycolysis in mammalian cells by preferentially arginylating HIF1α that is hydroxylated by PHD in the presence of oxygen. Furthermore, the degradation of arginylated HIF1α is independent of pVHL E3 ubiquitin ligase but dependent on the UBR family proteins. Bioinformatic analysis of human tumor data reveals that the ATE1/UBR and pVHL pathways jointly regulate oxygen sensing in a transcription-independent manner with different tissue specificities. Phylogenetic analysis suggests that eukaryotic ATE1 likely evolved during mitochondrial domestication, much earlier than pVHL.",
keywords = "ATE1, Arginylation, HIF1α, Warburg effect, arginyltransferase, degradation, glycolysis, hypoxic signaling, oxygen sensing, posttranslational protein modification",
author = "Moorthy, {Balaji T.} and Chunhua Jiang and Patel, {Devang M.} and Yuguang Ban and O'Shea, {Corin R.} and Akhilesh Kumar and Tan Yuan and Birnbaum, {Michael D.} and Gomes, {Aldrin V.} and Xi Chen and Flavia Fontanesi and Lampidis, {Theodore J.} and Antoni Barrientos and Fangliang Zhang",
note = "Funding Information: This study is supported in part by NIGMS / NIH R01GM138557 and a University of Miami startup funding awarded to F.Z. A.B. is supported by an NIGMS -MIRA ( R35GM118141 to A.B.) and a Muscular Dystrophy Association Research Grant ( MDA-381828 to A.B.). Funding Information: The access to a Seahorse analyzer and technical supports were provided by Drs. Howard Guy, Delcroix Ga?tan, and Medhi Wangpaichitr at the University of Miami (UM). Access to hypoxia chambers was provided by Drs. Claudia Rodrigues and Roberta Soares at UM. The flow cytometer was performed in the core facility of the Sylvester Comprehensive Cancer Center. A portion of mass spectrometry analysis was performed by Dr. Dale Chaput in the Proteomics Core Facility at the University of South Florida. This study is supported in part by NIGMS/NIH R01GM138557 and a University of Miami startup funding awarded to F.Z. A.B. is supported by an NIGMS-MIRA (R35GM118141 to A.B.) and a Muscular Dystrophy Association Research Grant (MDA-381828 to A.B.). The graphic abstract was adapted from ?NFAT Signaling pathway,? by BioRender.com (2022). Conceptualization, F.Z.; methodology, B.T.M. C.J. D.M.P. A.V.G. T.J.L. F.F. A.B. X.C. and F.Z.; investigation, B.T.M. C.J. D.M.P. Y.B. C.R.O. A.K. T.Y. M.D.B. A.V.G. F.F. and F.Z.; writing ? original draft, B.T.M. and F.Z.; writing ? review & editing, F.Z. F.F. T.J.L. A.B. and A.V.G.; funding acquisition, F.Z. and A.B.; resources, F.Z. A.B. F.F. T.J.L. and A.V.G.; supervision, F.Z. A.B. and F.F. The authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = mar,
day = "14",
doi = "10.1016/j.devcel.2022.02.010",
language = "English (US)",
volume = "57",
pages = "654--669.e9",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "5",
}