Deciphering the emerging role of SUMO conjugation in the hypoxia-signaling cascade

Biol Chem. 2013 Apr;394(4):459-69. doi: 10.1515/hsz-2012-0319.


By driving the primary transcriptional response, the hypoxia inducible factor (HIF) is a master player of the hypoxia-signaling cascade, activation of which is essential to maintain oxygen homeostasis. HIF is formed by the interaction of a constitutive HIF-1β subunit with a HIF-α subunit tightly regulated through the concerted action of the prolyl hydroxylase domain containing proteins (PHDs) and factor inhibiting HIF. In well-oxygenated cells, HIF-α prolyl-hydroxylation by PHDs is the recognition signal for the binding of the ubiquitin E3 ligase pVHL, allowing protein poly-ubiquitination and degradation by the proteasome. Factor inhibiting HIF-mediated asparaginyl hydroxylation prevents interaction with the CBP/p300 coactivator and hence reduces HIF-dependent transcriptional activity. Upon low oxygen availability, HIF-α hydroxylation is blocked, resulting in protein stabilization and HIF complex activation. Post-translational modifications other than hydroxylation appear to be important in the cellular response to hypoxia. Small ubiquitin-like modifier (SUMO) is a 10 kDa protein readily conjugated to the lysine (K) residues of numerous cellular substrates in a sequential process termed SUMOylation. Recent data support the idea that a fine balance in SUMOylation/deSUMOylation is required for the adequate activation of the hypoxia-signaling cascade. In the present review, we will concentrate on the mechanisms of SUMOylation and its consequences in the cellular response to hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Hypoxia / enzymology
  • Hypoxia / genetics
  • Hypoxia / metabolism*
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Sumoylation / genetics
  • Sumoylation / physiology*


  • Procollagen-Proline Dioxygenase