PHD1 Links Cell-Cycle Progression to Oxygen Sensing through Hydroxylation of the Centrosomal Protein Cep192

Moser, Sandra; Bensaddek, Dalila; Ortmann, Brian; Maure, Jean-François; Mudie, Sharon; Blow, J. Julian; Lamond, Angus I.; Swedlow, Jason R.; Rocha, Sónia

doi:10.1016/j.devcel.2013.06.014

Cited by 78 publications

(95 citation statements)

References 26 publications

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“…Only after 15 min, we observed a downregulation of the purine and pyrimidine metabolism, as well as genes encoding RNA polymerase subunits. Such a connection between cell cycle arrest and O2 limitation is wide spread and has been observed from E. coli to human cells (Douglas et al, 2001;Lee et al, 2001;Moser et al, 2013). According to our initial hypothesis, we expected that a rapid reoxygenation of the culture should at least partially inverse this regulation.…”

Section: −1mentioning

confidence: 75%

The novel globin protein fungoglobin is involved in low oxygen adaptation of Aspergillus fumigatus

Hillmann

Linde

Beckmann

et al. 2014

Molecular Microbiology

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SummaryThe human pathogenic fungus Aspergillus fumigatus normally lives as a soil saprophyte. Its environment includes poorly oxygenated substrates that also occur during tissue invasive growth of the fungus in the human host. Up to now, few cellular factors have been identified that allow the fungus to efficiently adapt its energy metabolism to hypoxia. Here, we cultivated A. fumigatus in an O2-controlled fermenter and analysed its responses to O2 limitation on a minute timescale. Transcriptome sequencing revealed several genes displaying a rapid and highly dynamic regulation. One of these genes was analysed in detail and found to encode fungoglobin, a previously uncharacterized member of the sensor globin protein family widely conserved in filamentous fungi. Besides low O2, iron limitation also induced transcription, but regulation was not entirely dependent on the two major transcription factors involved in adaptation to iron starvation and hypoxia, HapX and SrbA respectively. The protein was identified as a functional haemoglobin, as binding of this cofactor was detected for the recombinant protein. Gene deletion in A. fumigatus confirmed that haem-binding fungoglobins are important for growth in microaerobic environments with O 2 levels far lower than in hypoxic human tissue.

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Section: −1mentioning

confidence: 75%

The novel globin protein fungoglobin is involved in low oxygen adaptation of Aspergillus fumigatus

Hillmann

Linde

Beckmann

et al. 2014

Molecular Microbiology

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“…The observation that PHD2 interacts with, but apparently does not hydroxylate, eEF2, the eukaryotic counterpart to prokaryotic EF-G, an EF-Tu homolog (15), is interesting because it may reflect an ancestral relationship between PPHD and EF-Tu. Competition between HIF-α and eEF2 [and potentially other PHD substrates; e.g., pyruvate kinase M2 (38) or centrosomal protein 192 (39)], may help regulate the hypoxic response in higher animals. Analogous competition is proposed for factor-inhibiting HIF (FIH) catalyzed HIF-1α asparagine hydroxylation, which reduces HIF activity by blocking its interaction with coactivator proteins (1).…”

Section: Discussionmentioning

confidence: 99%

Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation

Scotti

Leung

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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The roles of 2-oxoglutarate (2OG)-dependent prolyl-hydroxylases in eukaryotes include collagen stabilization, hypoxia sensing, and translational regulation. The hypoxia-inducible factor (HIF) sensing system is conserved in animals, but not in other organisms. However, bioinformatics imply that 2OG-dependent prolyl-hydroxylases (PHDs) homologous to those acting as sensing components for the HIF system in animals occur in prokaryotes. We report cellular, biochemical, and crystallographic analyses revealing that Pseudomonas prolyl-hydroxylase domain containing protein (PPHD) contain a 2OG oxygenase related in structure and function to the animal PHDs. A Pseudomonas aeruginosa PPHD knockout mutant displays impaired growth in the presence of iron chelators and increased production of the virulence factor pyocyanin. We identify elongation factor Tu (EF-Tu) as a PPHD substrate, which undergoes prolyl-4-hydroxylation on its switch I loop. A crystal structure of PPHD reveals striking similarity to human PHD2 and a Chlamydomonas reinhardtii prolyl-4-hydroxylase. A crystal structure of PPHD complexed with intact EF-Tu reveals that major conformational changes occur in both PPHD and EF-Tu, including a >20-Å movement of the EF-Tu switch I loop. Comparison of the PPHD structures with those of HIF and collagen PHDs reveals conservation in substrate recognition despite diverse biological roles and origins. The observed changes will be useful in designing new types of 2OG oxygenase inhibitors based on various conformational states, rather than active site iron chelators, which make up most reported 2OG oxygenase inhibitors. Structurally informed phylogenetic analyses suggest that the role of prolylhydroxylation in human hypoxia sensing has ancient origins.T he hypoxia-inducible transcription factor (HIF) is a major regulator of the response to limited oxygen availability in humans and other animals (1-3). A hypoxia-sensing component of the HIF system is provided by 2-oxoglutarate (2OG)-dependent and Fe(II)-dependent oxygenases, which catalyze prolyl-4-hydroxylation of HIF-α subunits, a posttranslational modification that enhances binding of HIF-α to the von Hippel-Lindau protein (pVHL), so targeting HIF-α for proteasomal degradation. The HIF prolyl-hydroxylases (PHDs) belong to a subfamily of 2OG oxygenases that catalyze prolyl-hydroxylation, which also includes the collagen prolyl-3-hydroxylases (CP3Hs) and prolyl-4-hydroxylases (CP4Hs) (4). Subsequently identified prolyl-hydroxylases include the ribosomal prolyl-hydroxylases (OGFOD1 and Tpa1), which catalyze ribosomal protein 23 prolyl-3-hydroxylation in many eukaryotes, and slime-mold enzymes, which catalyze prolyl-4-hydroxylation of Skp1, a ubiquitin ligase subunit (5-9). The HIF-PHD-VHL triad is likely present in all animals, but probably not in other organisms (3). However, structurally informed bioinformatic analyses imply the presence of PHD homologs in bacteria (10, 11), including in Pseudomonas spp, suggesting PHDs may have ancient origins. ResultsPseudomonas spp. Cont...

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“…Reflecting the abundance of evidence relating to phosphorylation, this review focuses on the role of kinases and phosphatases at centrosomes and SPBs. Other post-translational modifications, including ubiquitylation, hydroxylation and acetylation, also occur at these organelles [30][31][32][33][34]; it seems safe to predict that the impact of these modifications will likely attract increasing interest in the future. The cell cycle control machinery is centred on cyclin-dependent kinases (Cdks) and conserved from yeast to human.…”

Section: Introductionmentioning

confidence: 99%

Centrosomes as signalling centres

Arquint

Gabryjonczyk

Nigg

2014

Phil. Trans. R. Soc. B

130

114

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Centrosomes—as well as the related spindle pole bodies (SPBs) of yeast—have been extensively studied from the perspective of their microtubule-organizing roles. Moreover, the biogenesis and duplication of these organelles have been the subject of much attention, and the importance of centrosomes and the centriole–ciliary apparatus for human disease is well recognized. Much less developed is our understanding of another facet of centrosomes and SPBs, namely their possible role as signalling centres. Yet, many signalling components, including kinases and phosphatases, have been associated with centrosomes and spindle poles, giving rise to the hypothesis that these organelles might serve as hubs for the integration and coordination of signalling pathways. In this review, we discuss a number of selected studies that bear on this notion. We cover different processes (cell cycle control, development, DNA damage response) and organisms (yeast, invertebrates and vertebrates), but have made no attempt to be comprehensive. This field is still young and although the concept of centrosomes and SPBs as signalling centres is attractive, it remains primarily a concept—in need of further scrutiny. We hope that this review will stimulate thought and experimentation.

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PHD1 Links Cell-Cycle Progression to Oxygen Sensing through Hydroxylation of the Centrosomal Protein Cep192

Cited by 78 publications

References 26 publications

The novel globin protein fungoglobin is involved in low oxygen adaptation of Aspergillus fumigatus

The novel globin protein fungoglobin is involved in low oxygen adaptation of Aspergillus fumigatus

Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation

Centrosomes as signalling centres

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