Abstract
Oxygen is essential for aerobic cells, and thus its sensing is critical for the optimal maintenance of vital cellular and tissue processes such as metabolism, pH homeostasis, and angiogenesis, among others. Hypoxia-inducible factors (HIFs) play central roles in oxygen sensing. Under hypoxic conditions, the α subunit of HIFs is stabilized and forms active heterodimers that translocate to the nucleus and regulate the expression of important sets of genes. This process, in turn, will induce several physiological changes intended to adapt to these new and adverse conditions. Over the last decades, numerous studies have reported a close relationship between viral infections and hypoxia. Interestingly, this relation is somewhat bidirectional, with some viruses inducing a hypoxic response to promote their replication, while others inhibit hypoxic cellular responses. Here, we review and discuss the cellular responses to hypoxia and discuss how HIFs can promote a wide range of physiological and transcriptional changes in the cell that modulate numerous human viral infections.
Highlights
Hypoxia is described as a reduction in the normal levels of oxygen due to a decreased availability or delivery of this gas to cells and tissues [1]
In cancer cells Hypoxia-inducible factors (HIFs)-1 and HIF-2 have been reported to downregulate the expression of proliferator-activated receptorγ coactivator-1α (PGC-1α), carnitine palmitoyltransferase 1A (CPT1A), and mediumand long-chain acyl-COA dehydrogenases (MACD and LACD), which are involved in β-oxidation inhibition [63,64]
Paracrine activation of mammalian target of rapamycin (mTOR) has been reported to promote the upregulation of HIF-1, which was accomplished by viral GPCR activation through multiple signaling pathways, such as those associated with Extracellular signal-regulated kinase (ERK) and AKT [146]
Summary
Hypoxia is described as a reduction in the normal levels of oxygen due to a decreased availability or delivery of this gas to cells and tissues [1]. Under normoxic conditions (normal oxygen conditions), FIH-1, which is an asparaginyl hydroxylase, hydroxylates an asparagine residue in the C-terminal transactivation domain (C-TAD), which prevents the recruitment of transcriptional coactivators that bind to this region within HIF-1α This process inhibits HIF-1α association with the transcriptional coactivator CBP/p300 and the transcriptional activation of HIF-1α [7,8]. HIF-1α at threonine 455 and HIF-2α at serine 435 These phosphorylations inhibit the ability of PHDs to bind and hydroxylate HIF-1α, promoting protein stabilization of these transcription factors [16]. Different studies have described that NO donors, macrophage-derived NO, NO synthase transfection, and increased endogenous NO via iNOS all induce HIF-1α accumulation and the transcription of HIF-1 target genes [18,19] This effect has been shown to be concentration-dependent, as some concentrations of NO have an inhibitory effect over HIF-1α stabilization [18]. We revise and discuss cellular responses to hypoxia and how viruses can modulate hypoxia-related genes in their favor
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