Comparative analysis of N-terminal cysteine dioxygenation and prolyl-hydroxylation as oxygen-sensing pathways in mammalian cells

In animals, adaptation to changes in cellular oxygen levels is coordinated largely by 2-oxoglutarate-dependent prolyl-hydroxylase domain (PHD) dioxygenase family members, which regulate the stability of their hypoxia-inducible factor (HIF) substrates to promote expression of genes that adapt cells t...

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Vydáno v:The Journal of biological chemistry Ročník 299; číslo 9; s. 105156
Hlavní autoři: Tian, Ya-Min, Holdship, Philip, To, Trang Quynh, Ratcliffe, Peter J., Keeley, Thomas P.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 01.09.2023
American Society for Biochemistry and Molecular Biology
Témata:
ADO
Animals
Cysteine - metabolism
dioxygenase
HIF
hydroxylase
Hydroxylation
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Mammals - metabolism
Oxygen - metabolism
PHD
Procollagen-Proline Dioxygenase - metabolism
sensing
Signal Transduction
hypoxia
sensing
HIF
dioxygenase
HPRT
ADO
hydroxylase
PHD
PCO
ISSN:0021-9258, 1083-351X, 1083-351X
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Popis
Shrnutí:In animals, adaptation to changes in cellular oxygen levels is coordinated largely by 2-oxoglutarate-dependent prolyl-hydroxylase domain (PHD) dioxygenase family members, which regulate the stability of their hypoxia-inducible factor (HIF) substrates to promote expression of genes that adapt cells to hypoxia. Recently, 2-aminoethanethiol dioxygenase (ADO) was identified as a novel O2-sensing enzyme in animals. Through N-terminal cysteine dioxygenation and the N-degron pathway, ADO regulates the stability of a set of non-transcription factor substrates; the regulators of G-protein signaling 4, 5. and 16 and interleukin-32. Here, we set out to compare and contrast the in cellulo characteristics of ADO and PHD enzymes in an attempt to better understand their co-evolution in animals. We find that ADO operates to regulate the stability of its substrates rapidly and with similar O2-sensitivity to the PHD/HIF pathway. ADO appeared less sensitive to iron chelating agents or transition metal exposure than the PHD enzymes, possibly due to tighter catalytic-site Fe2+ coordination. Unlike the PHD/HIF pathway, the ADO/N-degron pathway was not subject to feedback by hypoxic induction of ADO, and induction of ADO substrates was well sustained in response to prolonged hypoxia. The data also reveal strong interactions between proteolytic regulation of targets by ADO and transcriptional induction of those targets, that shape integrated cellular responses to hypoxia. Collectively, our comparative analysis provides further insight into ADO/N-degron-mediated oxygen sensing and its integration into established mechanisms of oxygen homeostasis.
Bibliografie:ObjectType-Article-1
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content type line 23
ISSN:0021-9258
1083-351X
1083-351X
DOI:10.1016/j.jbc.2023.105156