The Asparagine Hydroxylase FIH: A Unique Oxygen Sensor

Abstract

Significance: Limited oxygen availability (hypoxia) commonly occurs in a range of physiological and pathophysiological conditions, including embryonic development, physical exercise, inflammation, and ischemia. It is thus vital for cells and tissues to monitor their local oxygen availability to be able to adjust in case the oxygen supply is decreased. The cellular oxygen sensor factor inhibiting hypoxiainducible factor (FIH) is the only known asparagine hydroxylase with hypoxia sensitivity. FIH uniquely combines oxygen and peroxide sensitivity, serving as an oxygen and oxidant sensor. Recent Advances: FIH was first discovered in the hypoxia-inducible factor (HIF) pathway as a modulator of HIF transactivation activity. Several other FIH substrates have now been identified outside the HIF pathway. Moreover, FIH enzymatic activity is highly promiscuous and not limited to asparagine hydroxylation. This includes the FIH-mediated catalysis of an oxygen-dependent stable (likely covalent) bond formation between FIH and selected substrate proteins (called oxomers [oxygen-dependent stable protein oligomers]). Critical Issues: The (patho-)physiological function of FIH is only beginning to be understood and appears to be complex. Selective pharmacologic inhibition of FIH over other oxygen sensors is possible, opening new avenues for therapeutic targeting of hypoxia-associated diseases, increasing the interest in its (patho-)physiological relevance. Future Directions: The contribution of FIH enzymatic activity to disease development and progression should be analyzed in more detail, including the assessment of underlying molecular mechanisms and relevant FIH substrate proteins. Also, the molecular mechanism(s) involved in the physiological functions of FIH remain(s) to be determined. Furthermore, the therapeutic potential of recently developed FIH-selective pharmacologic inhibitors will need detailed assessment. Antioxid.

The effect of HIF on metabolism and immunity

“…The HIF pathway is also regulated through the formation of the HIF transcriptional complex — a process that requires assembly of the HIF1α and HIF2α subunits with their transcriptional co-activators (CBP and p300) and recruitment of RNA polymerase 2. As mentioned earlier, the affinity of the HIF α-subunit for CBP and p300 is controlled by the HIF hydroxylase FIH, whereby FIH-mediated hydroxylation of an asparagine residue in HIFα reduces the affinity of HIF for CBP and p300 (refs 38 – 40 , 43 , 78 , 79 ).…”

“…1 ). Hydroxylation by the 2-oxoglutarate-dependent factor inhibiting HIF (FIH, encoded by HIF1AN ) renders the HIF α-subunits unable to bind to their transcriptional co-activators, the histone acetyl transferases CBP and p300, preventing the formation of a functional transcriptional complex and thereby repressing HIF activity in an oxygen-dependent manner 43 . Under conditions of hypoxia, however, the enzymatic activity of the PHD and FIH HIF hydroxylases is reduced, thereby stabilizing the HIF α-subunits and increasing their transcriptional activity, respectively.…”

The Oxygen Cascade from Atmosphere to Mitochondria as a Tool to Understand the (Mal)adaptation to Hypoxia

“…HIF activity is only in small part regulated by gene expression, with the bulk of the control entrusted to prolyl hydroxylases (PHD) and the factor inhibiting HIF (FIH), which, in the presence of O 2 , hydroxylate HIF at either the two prolyl or the asparaginyl residues, respectively [ 29 ]. When hydroxylated, HIF undergoes ubiquitination and cannot be active in its task of controlling the gene expression.…”

Fount, fate, features, and function of renal erythropoietin-producing cells

“…Non-hydroxylated HIFα heterodimerizes with the common HIF-β subunit and forms a transcriptional enhancer complex at hypoxia response elements (HREs) of HIF target genes. PHD2 and PHD3 are among these genes, establishing a negative feedback loop that limits HIF activity and adapts the hypoxic set point to the microenvironmental oxygen partial pressure HIF (FIH), another HIF hydroxylase, is apparently not involved in Epo regulation [114,124]. Like the collagen hydroxylases, HIFα hydroxylases are sensitive to oxidation and require ascorbate (vitamin C) as a co-factor.…”

“…1 , the α subunits of these heterodimeric transcription factors are oxygen-labile, marked for degradation by oxygen-dependent prolyl-4-hydroxylases (PHDs) and conveyed to the ubiquitin–proteasome system by the von Hippel-Lindau (VHL) tumor suppressor protein [ 89 ]. Factor inhibiting HIF (FIH), another HIF hydroxylase, is apparently not involved in Epo regulation [ 114 , 124 ]. Like the collagen hydroxylases, HIFα hydroxylases are sensitive to oxidation and require ascorbate (vitamin C) as a co-factor.…”