Evolutionary origins of oxygen sensing in animals.

all animal life requires molecular oxy­ gen as the terminal electron acceptor in aerobic energy production. a lack of oxygen can reduce the rate of energy pro­ duction, whereas an excess of oxygen leads to the accumulation of toxic reactive oxy­ gen species. Hence, animals have evolved sophisticated mechanisms with which to monitor and respond to fluctu ations in oxygen availability, in order to maintain cellular homeostasis. in all animal taxa examined so far, the maintenance of physio­ logical oxygen homeostasis is mediated by the oxygen­dependent post­translational hydroxylation of a heterodimeric tran­ scription factor, termed hypoxia­ inducible factor (HiF; Kaelin & ratcliffe, 2008). the hydroxylation reaction is catalysed by pro­ lyl hydroxy lase (pHD) enzymes, which are direct sensors of cellular oxygen tension. under normoxia, HiFα is hydroxylated in a pHD­dependent manner, which leads to its ubiquitination by the von Hippel–lindau protein (VHl) and proteasomal degrada­ tion. under hypoxia, the hydroxylase activ­ ity of pHD enzymes is inhibited, thereby allowing the stable formation of the hetero­ dimeric HiF transcription factor and its activation. HiF is then translocated to the nucleus where it activates the transcription of numerous target genes involved in pro­ cesses that enhance oxygen delivery—such as erythropoiesis and angiogenesis—or improve prospects for survival under hypoxia, by altering energy metabolism. the evolutionary origins of this central physiological regulatory system have been unclear, as the regulatory interactions of the constituent HiF and pHD genes have not been experimentally characterized in non­bilaterian animals. in this issue of EMBo reports, the Schofield lab demon­ strate that the HiF system has a regulatory oxygen­sensing function in the simplest known animal, the placozoan Trichoplax adhaerens (loenarz et al, 2010). the ances­ tors of T. adhaerens seem to have diverged from the lineage leading to bilaterian ani­ mals more than 550 million years ago, in the precambrian. loenarz and colleagues conducted a comparative genomic analysis revealing that the three main components of the HiF system—HiF, pHD and VHl—are present in all the metazoans, including T. adhaerens, but are not found in non­ metazoan taxa such as choano flagellates or other pro­ tists. the authors then demonstrated that T. adhaerens HiFα has an oxygen­ dependent degradation (oDD) domain containing the critical proline residue that is hydroxy­ lated by pHD. this proline­containing oDD domain sets HiFα apart from other Evolutionary origins of oxygen sensing in animals