The Role of Hypoxia-Inducible Factor Post-Translational Modifications in Regulating its Localisation, Stability and Activity

Albanese, Adam; Daly, Leonard A.; Mennerich, Daniela; Kietzmann, Thomas; Sée, Violaine

doi:10.20944/preprints202012.0112.v1

Cited by 18 publications

(1 citation statement)

References 116 publications

(141 reference statements)

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“…Surprisingly, even though there is ample evidence for an important role of HIF-1α induction during infection with various Leishmania species (Alonso et al, 2019;Arrais-Silva et al, 2005;Hammami et al, 2017;Hammami et al, 2015;Mesquita et al, 2020;Rocha et al, 2018;Weinkopff et al, 2019), expression and protein abundance of this TF were neither altered in ivLIMs nor evLIMs, suggesting alternative forms of regulation. While we cannot rule out possible post-translational modifications that may alter HIF1-α TF activity (Albanese et al, 2020), we identified the m 6 A reader protein IGF2BP2 as a possible key regulator underlying HIF-1α-independent LIMs metabolic reprogramming. This mRNA-binding protein is known to control glycolytic metabolisms by stabilizing various transcripts of the glycolytic pathway, including m 6 A modified Ldha, AldoA or Hk2 transcripts (Liu et al, 2021;Wu et al, 2023;Zhou et al, 2024).…”

Section: Discussionmentioning

confidence: 83%

The m⁶A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages

Zhang

Lecœur

Varet

et al. 2022

Preprint

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Macrophages are the major host cells of the protozoan parasite Leishmania in mammalian infection. These key innate immune cells display remarkable phenotypic plasticity ranging from pro-inflammatory M1 to anti-inflammatory M2 macrophages that can control infection and tissue homeostasis, respectively. It has been recognized that Leishmania exploits macrophage phenotypic plasticity to establish chronic infection. However, the current notion that these parasites simply trigger an M2-like phenotype seems over-simplified considering the immunopathology observed during leishmaniasis, is which often characterized by a mixed Th1/Th2 immune response. Here we combined a series of systems-level analyses to shed new light on the phenotype of Leishmania-infected macrophages (LIMs). Immunometabolic profiling by RNAseq, quantitative RT-qPCR, cytokine immunoassays, and bioenergetic flux analysis of Leishmania amazonensis-infected bone marrow-derived macrophages (BMDMs) revealed a highly complex, mixed polarization phenotype and a unique bioenergetic signature. In vitro LIMs were characterized by (i) co-expression of both M1 and M2 markers at RNA and protein levels, (ii) expression changes of a unique set of inflammatory genes (e.g. RELA, IGFBP3, VEGFA), and (iii) modulation of metabolic gene expression, including up regulation of glycolytic genes. This LIMs-specific phenotype persisted for at least 30 days and was confirmed in vivo in lesion-isolated LIMs. Likewise, in vitro LIMs showed a mixed bioenergetic profile, increasing both glycolytic activity and oxidative phosphorylation (OXPHOS) compared to uninfected, nonpolarized macrophages (M0). Surprisingly, the elimination of intracellular parasites using the fast-acting, anti-leishmanial drug L-leucine-O-methyl ester (LME) enhanced both bioenergetic pathways to levels comparable to M1 (glycolysis) and M2 (OXPHOS) macrophages as soon as one hour after treatment, suggesting that L. amazonensis limits in real-time energy metabolism and ATP production in LIMs. In conclusion, L. amazonensis infection establishes a mixed, immunometabolomic polarization profile in infected BMDMs and lesional macrophages that on one hand can promote an M1-regulated Th1 response required for the recruitment of new host cells to infected tissues, while at the same time promoting an M2 phenotype that dampens pro-inflammatory immune-signaling and shields intracellular parasites from leishmanicidal Nitric Oxide (NO).

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Section: Discussionmentioning

confidence: 83%

The m⁶A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages

Zhang

Lecœur

Varet

et al. 2022

Preprint

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The glucocorticoid dexamethasone inhibits HIF-1alpha stabilisation and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages

Clayton,

Lockwood,

O’Neil

et al. 2023

Preprint

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Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis, caused by changes of glucose traffic and metabolism in muscle, liver and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly-used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on alteration of glucose utilisation.

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A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression

Sbaffone,

Jaffrain-Rea,

Cappabianca

et al. 2024

Biology

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Pituitary neuroendocrine tumors (PitNETs) are generally benign but comprise an aggressive, invasive, therapy-resistant, metastatic subset, underpinning a need for novel therapeutic targets. PitNETs exhibit low mutation rates but are associated with conditions linked to alternative splicing, an alternative oncogene pathway activation mechanism. PitNETs express the neurotrophin receptor TrkA, which exhibits oncogenic alternative TrkAIII splicing in other neuroendocrine tumors. We, therefore, assessed whether TrkAIII splicing represents a potential oncogenic participant in PitNETs. TrkAIII splicing was RT-PCR assessed in 53 PitNETs and TrkA isoform(s) expression and activation were assessed by confocal immunofluorescence. TrkAIII splicing was also compared to HIF1α, HIF2α, SF3B1, SRSF2, U2AF1, and JCPyV large T antigen mRNA expression, Xbp1 splicing, and SF3B1 mutation. TrkAIII splicing was detected in all invasive and most non-invasive PitNETs and was significantly elevated in invasive cases. In PitNET lineages, TrkAIII splicing was significantly elevated in invasive PIT1 PitNETs and high in invasive and non-invasive SF1 and TPIT lineages. Immunoreactivity consistent with TrkAIII activation characterized PitNET expressing TrkAIII mRNA, and invasive Pit1 PitNETs exhibited elevated HIF2α expression. TrkAIII splicing did not associate with SF3B1 mutations, altered SF3B1, SRSF2, and U2AF1 or JCPyV large T antigen expression, or Xbp1 splicing. Therefore, TrkAIII splicing is common in PitNETs, is elevated in invasive, especially PIT1 tumors, can result in intracellular TrkAIII activation, and may involve hypoxia. The data support a role for TrkAIII splicing in PitNET pathogenesis and progression and identify TrkAIII as a novel potential target in refractory PitNETs.

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The Role of Hypoxia-Inducible Factor Post-Translational Modifications in Regulating its Localisation, Stability and Activity

Cited by 18 publications

References 116 publications

The m⁶A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages

The m⁶A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages

The glucocorticoid dexamethasone inhibits HIF-1alpha stabilisation and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages

A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression

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The Role of Hypoxia-Inducible Factor Post-Translational Modifications in Regulating its Localisation, Stability and Activity

Cited by 18 publications

References 116 publications

The m6A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages

The m6A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages

The glucocorticoid dexamethasone inhibits HIF-1alpha stabilisation and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages

A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression

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The m⁶A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages

The m⁶A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages