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

Abstract

The hypoxia signalling pathway enables adaptation of cells to decreased oxygen availability. When oxygen becomes limiting, the central transcription factors of the pathway, hypoxia-inducible factors (HIFs), are stabilised and activated to induce the expression of hypoxia-regulated genes, thereby maintaining cellular homeostasis. Whilst hydroxylation has been thoroughly described as the major and canonical modification of the HIF-α subunits, regulating both HIF stability and activity, a range of other post-translational modifications decorating the entire protein play also a crucial role in altering HIF localisation, stability, and activity. These modifications, their conservation throughout evolution, and their effects on HIF-dependent signalling are discussed in this review.

Keywords: HIF-1α; HIF-2α; S-nitrosylation; acetylation; cysteine phosphorylation; hypoxia; methylation; phosphorylation; posttranslational modifications; signalling; sumoylation; ubiquitination.

Figure 1

The canonical oxygen-dependent degradation mechanism for HIF-α by pVHL-mediated 26S proteasomal degradation and its inhibition by Factor-Inhibiting HIF (FIH) during hypoxia.

Figure 2

Localisation and function of non-canonical HIF-α post-translational modifications (PTMs) mapped onto full-length HIF-1α (A) and HIF-2α (B). When a given PTM has multiple publications stating conflicting functional outcomes, then the functionality is denoted as ‘controversial’.

Figure 3

The intracellular protein-dependent cell signalling for the transcriptional, translational, and phosphorylation-dependent regulation of HIF-α. Purple arrows indicate protein kinases that directly phosphorylate HIF-α.

Figure 4

The amino acid sites of HIF-α subjected to acetylation and the acetyltransferase enzymes attributed to the relevant sites. A ‘?’ represents an unknown regulator, not currently described in the literature. PTMs with yellow and blue backgrounds indicate activatory and inhibitory effects, respectively.

Figure 5

The amino acid sites of HIF-α methylation and the methyltransferase enzymes responsible for each site-specific modification. PTMs with yellow and blue backgrounds indicate activatory and inhibitory effects, respectively.