HIF activation by pH-dependent nucleolar sequestration of VHL

Mekhail, Karim; Gunaratnam, Lakshman; Bonicalzi, Marie Eve; Lee, Stephen

doi:10.1038/ncb1144

Cited by 240 publications

(234 citation statements)

References 29 publications

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“…Indeed, we find that ablation of LDHA and MDH2 abrogates the ability of acidotic cells to stabilize HIF-1α. It is also possible that acidification and L-2HG cooperate in the stabilization of HIF-1α 50 . Compared to L-2HG, we observed approximately 10 fold lower intracellular concentrations of D-2HG.…”

Section: Discussionmentioning

confidence: 99%

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via ‘promiscuous’ reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.

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Section: Discussionmentioning

confidence: 99%

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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“…Recently, an additional protein retention mechanism based on GTP-driven cycles has been identified for nucleostemin (121). The GTP-GDP exchange mechanism is not the only intracellular signal able to move nucleolar proteins: stimuli as the hydrogen ion were already described by Mekhail et al (98), who demonstrated how the nucleolar sequestration of the von Hippel-Lindau protein after a pH change promotes the stabilization of the hypoxia-inducible factor, triggering a general cell response to hypoxic conditions (115).…”

Section: The Way To Move: Visitors Versus Resident Nucleolar Proteinsmentioning

confidence: 98%

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Antoniali

Lirussi

Poletto

et al. 2014

Antioxidants & Redox Signaling

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Significance: An emerging concept in DNA repair mechanisms is the evidence that some key enzymes, besides their role in the maintenance of genome stability, display also unexpected noncanonical functions associated with RNA metabolism in specific subcellular districts (e.g., nucleoli). During the evolution of these key enzymes, the acquisition of unfolded domains significantly amplified the possibility to interact with different partners and substrates, possibly explaining their phylogenetic gain of functions. Recent Advances: After nucleolar stress or DNA damage, many DNA repair proteins can freely relocalize from nucleoli to the nucleoplasm. This process may represent a surveillance mechanism to monitor the synthesis and correct assembly of ribosomal units affecting cell cycle progression or inducing p53-mediated apoptosis or senescence. Critical Issues: A paradigm for this kind of regulation is represented by some enzymes of the DNA base excision repair (BER) pathway, such as apurinic/apyrimidinic endonuclease 1 (APE1). In this review, the role of the nucleolus and the noncanonical functions of the APE1 protein are discussed in light of their possible implications in human pathologies. Future Directions: A productive cross-talk between DNA repair enzymes and proteins involved in RNA metabolism seems reasonable as the nucleolus is emerging as a dynamic functional hub that coordinates cell growth arrest and DNA repair mechanisms. These findings will drive further analyses on other BER proteins and might imply that nucleic acid processing enzymes are more versatile than originally thought having evolved DNA-targeted functions after a previous life in the early RNA world. Antioxid. Redox Signal. 20, 621-639.

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“…In addition to hypoxia, two important events in T cell activation, signaling by phosphoinositide 3-kinases and cytoplasmic acidification, are known to induce HIF-1␣ protein expression (40)(41)(42). It should also be noted that tissue oxygen tensions are likely relatively ''hypoxic'' compared with atmospheric oxygen tensions used for in vitro tissue culture.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Neumann

Yang

Biju

et al. 2005

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

107

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Low oxygen pressures exist in many solid tissues, including primary and secondary lymphoid organs. One key element in cellular adaptation to hypoxia is induced expression of hypoxia inducible factor (Hif) 1␣. Here, we have examined the effect of Hif-1␣, isolated from the myriad other effects of hypoxia, on T cell receptor (TCR) signaling in thymocytes. Because pVHL (von Hippel-Lindau protein) directs the proteolysis of Hif-1␣ under ''normoxic'' conditions, we achieved constitutive stabilization of Hif-1␣ through thymic deletion of Vhlh and reversed Hif-1␣ stabilization with double deletion of Vhlh and Hif-1␣. We found that constitutive activity of Hif-1␣ resulted in diminished Ca 2؉ response upon TCR crosslinking despite equivalent activation of phospholipase C␥1, normal intracellular Ca 2؉ stores, and normal entry of Ca 2؉ across the plasma membrane. Altered Ca 2؉ response was instead due to accelerated removal of Ca 2؉ from the cytoplasm into intracellular compartments, which occurred in association with Hif-1␣-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic͞ endoplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1␣, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.calcium ͉ lymphocytes

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HIF activation by pH-dependent nucleolar sequestration of VHL

Cited by 240 publications

References 29 publications

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

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