Bound by Oxygen

Science Signaling  25 Oct 2011:
Vol. 4, Issue 196, pp. ec297
DOI: 10.1126/scisignal.4196ec297

In the fission yeast Schizosaccharomyces pombe, the transcription factor Sre1N is proteasomally degraded in the presence of oxygen (normoxia), a process that requires the C terminus of the dioxygenase Ofd1. When oxygen is low or absent (hypoxia), Nro1 binds to the C-terminal domain of Ofd1 (an interaction that is regulated by the N-terminal dioxygenase domain of Ofd1, which acts as an oxygen sensor) and blocks the ability of Ofd1 to promote degradation of Sre1N. Thus, Sre1 accumulates and activates the expression of genes encoding factors that enable cells to cope with a lack of oxygen. In seeking to identify the E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase required for the proteasomal degradation of Sre1N, Lee et al. (see also the commentary by Osborne) found that Ofd1 also inhibited the activity of Sre1N in a manner that was degradation independent. Hypoxic cells showed increased expression of the Sre1N target gene hem13+ compared with cells under normal oxygen, a response that required Nro1. Deletion of ofd1+ or pharmacological inhibition of the dioxygenase activity of Ofd1 increased Sre1N binding to the promoter of a reporter gene of Sre1N transcriptional activity. In addition, Sre1N binding to the promoters of four target genes in normoxic cells was increased by deletion of ofd1+ and decreased by deletion of nro1+. Binding of Sre1N to the hem13+ promoter and binding of Nro1 to Ofd1 concomitantly started to increase after cells were shifted to low oxygen. In cells expressing a form of Ofd1 with a mutation in the iron-coordinating site (H142A) of the dioxygenase domain, hypoxia did not induce binding of the mutant form of Ofd1 to Nro1, an increase in hem13+ expression, or binding of Sre1N to the hem13+ promoter. The C-terminal domain of Ofd1 bound to a region of Sre1N that contains the basic helix-loop-helix DNA binding domain, and overexpression of the C-terminal domain of Ofd1 decreased the binding of Sre1N to the heme13+ promoter in cells and in vitro. Thus, during normoxia, Ofd1 attenuates the activity of Sre1N by promoting its proteasomal degradation and inhibiting its transcriptional activity. During hypoxia, Nro1 binds to and inhibits Ofd1, thereby stabilizing Sre1N and enabling changes in gene expression in response to low oxygen.

C.-Y. S. Lee, T.-L. Yeh, B. T. Hughes, P. J. Espenshade, Regulation of the Sre1 hypoxic transcription factor by oxygen-dependent control of DNA binding. Mol. Cell 44, 225–234 (2011). [PubMed]

T. F. Osborne, Sterols for oxygen: The metabolic burden of microbial SREBP. Mol. Cell 44, 172–174 (2011). [PubMed]