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Review
. 2020 Oct 26;9(11):2359.
doi: 10.3390/cells9112359.

The Role of Sumoylation in the Response to Hypoxia: An Overview

Chrysa Filippopoulou  1 , George Simos  1   2 , Georgia Chachami  1
Affiliations
Review

The Role of Sumoylation in the Response to Hypoxia: An Overview

Chrysa Filippopoulou et al. Cells. .

Abstract

Sumoylation is the covalent attachment of the small ubiquitin-related modifier (SUMO) to a vast variety of proteins in order to modulate their function. Sumoylation has emerged as an important modification with a regulatory role in the cellular response to different types of stress including osmotic, hypoxic and oxidative stress. Hypoxia can occur under physiological or pathological conditions, such as ischemia and cancer, as a result of an oxygen imbalance caused by low supply and/or increased consumption. The hypoxia inducible factors (HIFs), and the proteins that regulate their fate, are critical molecular mediators of the response to hypoxia and modulate procedures such as glucose and lipid metabolism, angiogenesis, erythropoiesis and, in the case of cancer, tumor progression and metastasis. Here, we provide an overview of the sumoylation-dependent mechanisms that are activated under hypoxia and the way they influence key players of the hypoxic response pathway. As hypoxia is a hallmark of many diseases, understanding the interrelated connections between the SUMO and the hypoxic signaling pathways can open the way for future molecular therapeutic interventions.

Keywords: HIF; HIF-1α; SUMO; hypoxia; oxygen homeostasis; sumoylation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The SUMO conjugation mechanism. Initially the SUMO precursor form is proteolytically cleaved (by SUMO-specific proteases) to expose the C-terminal glycine–glycine (GG) motif. Mature SUMO is activated by the SUMO E1 heterodimer SAE1/SAE2 (Aos1/Uba2) in an ATP-dependent manner, then a thioester bond is formed between the C-terminal glycine of SUMO and the catalytic cysteine (-SH) of SAE2. SUMO is subsequently loaded to the catalytic cysteine of the SUMO E2 enzyme Ubc9. Ubc9 catalyzes formation of an isopeptide bond between the C-terminal glycine of SUMO and a lysine residue in the substrate. This procedure is usually facilitated by a SUMO E3 ligase. Sumoylation can occur as mono-sumoylation, poly-mono-sumoylation or polysumoylation (formation of sumo chains) on target substrates. Sumoylation is reversed by SUMO-specific proteases that cleave the isopeptide bond and release SUMO.
Figure 2
Figure 2
The hypoxic signaling pathway. The hypoxic signaling pathway: Under normoxia HIFα is hydroxylated by PHD and FIH hydroxylases in an oxygen dependent manner. Hydroxylation by PHD leads to pVHL and E3 ubiquitin ligase recruitment, ubiquitination of HIFα and subsequent proteasomal degradation. Hydroxylation by FIH leads to transcriptional inactivation. Low O2 inactivates both PHD and FIH hydroxylases, HIFα is stabilized, enters the nucleus, dimerizes with HIF-1β (ARNT), binds to specific DNA elements (hypoxia responsive elements) and, in association with transcription coactivators such as CBP/p300, stimulates the transcription of hypoxia target genes.
Figure 3
Figure 3
Schematic representation of the association of hypoxic signaling agents with SUMO and its effect on hypoxia inducible factor (HIF) stability and activity. (A) HIFα sumoylation affects its transcriptional activity. E3 ligases PIAS3, Cbx4 and RSUME may mediate sumoylation and activation of HIF-1, while HIF-1α sumoylation by E3 ligase PIASy may lead to its proteasomal degradation. Desumoylation of HIF-1α by sumo isopeptidase SENP1 may lead to stabilization. HIF-2α sumo modification leads to VHL and RNF4 dependent ubiquitination and proteasomal degradation. (B) Sumoylation of HIFα hydroxylases affects their activity. Modification of PHD3 causes inhibition of HIF-1 transcriptional activity, without, however, affecting HIF-1α protein stability. Sumoylation of FIH promotes its proteasomal degradation, thus enhancing the transcriptional activity of HIF-1α. (C) Sumoylation of p300 and CBP affects HIF-1 activity. SUMO conjugation of p300 or CBP leads to transcriptional repression of HIF-1 target genes mediated by SUMO-dependent recruitment of HDAC6 and HDAC2/DAXX, respectively. (D) Sumoylation of pVHL by PIASy promotes its deactivation leading to HIF stabilization and activation. Relevant references and details can be found in Table 1.
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