Oxygen-sensing mechanisms in development and tissue repair

Abstract

Under normoxia, hypoxia inducible factor (HIF) α subunits are hydroxylated by PHDs (prolyl hydroxylase domain proteins) and subsequently undergo polyubiquitylation and degradation. Normal embryogenesis occurs under hypoxia, which suppresses PHD activities and allows HIFα to stabilize and regulate development. In this Primer, we explain molecular mechanisms of the oxygen-sensing pathway, summarize HIF-regulated downstream events, discuss loss-of-function phenotypes primarily in mouse development, and highlight clinical relevance to angiogenesis and tissue repair.

Oxygen is an essential gasotransmitter directly sensed via protein gasoreceptors

“…However, the majority of recent scientific literature on O 2 -sensing mechanisms (on plants or mammals), including notable announcements such as the 2019 Nobel Prize award in the field of physiology or medicine, does not mention a protein-based receptor for O 2 . 8,[16][17][18][19][20] This scenario reminds me of Plato's allegory of the cave, sensing. This is essential for raising awareness about the role of O 2 receptors, not only among scientists but also among students who switch to nonlibrary-based sources of scientific information.…”

“…However, the majority of recent scientific literature on O 2 ‐sensing mechanisms (on plants or mammals), including notable announcements such as the 2019 Nobel Prize award in the field of physiology or medicine, does not mention a protein‐based receptor for O 2 . 8 , 16 , 17 , 18 , 19 , 20 This scenario reminds me of Plato’s allegory of the cave, and we are still tied down by the weight and prestige of such awards and scientific journals. If bacteria have O 2 ‐sensing protein receptors such as DosP (direct sensor of O 2 , an O 2 ‐binding heme‐based phosphodiesterase) or FixL* (truncated sensor protein FixL, an O 2 ‐binding heme‐based kinase), or FNR (fumarate and nitrate reductase, an O 2 ‐binding iron–sulfur cluster‐based transcriptional activator), then it is very likely that other organisms also possess O 2 ‐binding protein receptors with diverse signaling domains and/or DNA‐binding transcriptional factors.…”

Tailless and hypoxia inducible factor-2α cooperate to sustain proangiogenic states of retinal astrocytes in neonatal mice

“…At the molecular level, retinal astrocyte differentiation is controlled, at least in part, by oxygen sensing mechanisms ( Bruick and McKnight, 2001 ; Carmeliet et al, 1998 ; Duan and Fong, 2019 ; Duan et al, 2017 , 2014 ; Epstein et al, 2001 ; Ivan et al, 2002 ; Maxwell et al, 1999 ; Perelli et al, 2021 ; Wang and Semenza, 1995 ; West et al, 2005 ). Oxygen sensing and hypoxia responses are ubiquitous processes in different types of cells, and are mediated by prolyl hydroxylase domain proteins (PHDs, also known as Egg Laying Nine or EGLN) and hypoxia inducible factor (HIF)-α proteins ( Bruick and McKnight, 2001 ; Carmeliet et al, 1998 ; Epstein et al, 2001 ; Ivan et al, 2002 ; Jiang et al, 2021 ; Maltepe et al, 1997 ; Peng et al, 2000 ; Tian et al, 1998 , 1997 ; Wang et al, 1995 ). In well oxygenated tissues, PHDs catalyze prolyl hydroxylation of HIF-α proteins, labeling them for pVHL and E3 ligase dependent polyubiquitination and proteasomal degradation.…”

Extracellular Vesicles That Herald the Scarcity of Oxygen

“…While the level of the β subunit, HIF-1β, does not fluctuate considerably, that of the α subunit, HIF-1α, markedly increases posttranslationally as cells face the scarcity of oxygen. Under the normal range of oxygen tension, HIF-1α is hydroxylated at the two proline residues in the ODD domain, P402 and P564, by the coordinated activity of the prolyl hydroxylase domain-con-taining proteins [16]. The resultant hydroxylated HIF-1α is bound and ubiquitinated by the von Hippel-Lindau complex of E3 ubiquitin ligase, subsequently undergoing degradation by the proteosome [16].…”

“…Under the normal range of oxygen tension, HIF-1α is hydroxylated at the two proline residues in the ODD domain, P402 and P564, by the coordinated activity of the prolyl hydroxylase domain-con-taining proteins [16]. The resultant hydroxylated HIF-1α is bound and ubiquitinated by the von Hippel-Lindau complex of E3 ubiquitin ligase, subsequently undergoing degradation by the proteosome [16]. As a result of this active removal of the α subunit, the functioning HIF-1 heterodimer, composed of HIF-1α and HIF-1β, does not form when oxygen is sufficiently available.…”