Physiological and pathological views of peroxiredoxin 4

• PRDX4 uniquely possesses a hydrophobic signal peptide at the amino terminus.
• PRDX4 functions as a sulfoxidase in endoplasmic reticulum.
• A variant form of PRDX4 is expressed only in testes.
• The roles of PRDX4 in the extracellular space need to be clarified.

Peroxiredoxins (PRDXs) form an enzyme family that exhibits peroxidase activity using electrons from thioredoxin and other donor molecules. As the signaling roles of hydrogen peroxide in response to extracellular stimuli have emerged, the involvement of PRDX in the hydrogen peroxide-mediated signaling has become evident. Among six PRDX members in mammalian cells, PRDX4 uniquely possesses a hydrophobic signal peptide at the amino terminus, and, hence, it undergoes either secretion or retention by the endoplasmic reticulum (ER) lumen. The role of PRDX4 as a sulfoxidase in ER is now attracting much attention regarding the oxidative protein folding of nascent proteins. Contrary to this role in the ER, the functional significance of PRDX4 in the extracellular milieu is virtually unknown despite its implications as a biomarker under pathological conditions in some diseases. Other than its systemically expressed form, a variant form of PRDX4 is transcribed from the upstream promoter/exon 1 of the systemic promoter/exon 1 and is uniquely expressed in sexually matured testes. Circumstantial evidence, together with deduced functions from the systemic form, suggests that there are potential roles for testicular PRDX4 in the reproductive processes such as the regulation of hormonal signals and the oxidative packaging of sperm chromatin. Elucidation of these PRDX4 functions under in vivo situations is expected to show the whole picture of how PRDX4 has evolved in multicellular organisms.

Roles for PRDX4 in ROS signaling and oxidative protein folding in the ER.In the cytoplasm, PRDX4 suppressively regulates phosphorylation signals from receptor tyrosine kinases such as GCSFR. In the endoplasmic reticulum (ER), PRDX4 in conjunction with ERO1 introduces a disulfide bond in the nascent protein via the oxidation of PDI family proteins. Figure optionsDownload high-quality image (164 K)Download as PowerPoint slide