A comprehensive review of peroxiredoxin 4, a redox protein evolved in oxidative protein folding coupled with hydrogen peroxide detoxification.

Peroxiredoxin (PRDX) primarily employs electrons from thioredoxin in order to reduce peroxides. PRDX4 mainly resides either in the endoplasmic reticulum (ER) lumen or in extracellular spaces. Due to the usage of alternative promoters, a first exon is transcribed from different regions of the Prdx4 gene, which results in two types of mRNAs. The first type is designated as Prdx4. It is translated with a cleavable, hydrophobic signal sequence and is expressed in most cells throughout the body. The second type is designated as Prdx4t. The peroxidase activity of PRDX4 is involved in both the reduction of hydrogen peroxides and in the oxidative folding of nascent proteins in the ER. Prdx4 appears to have evolved from an ancestral gene in Eutherians simultaneously with the evolution of sperm protamine to cysteine-rich peptides, and, therefore, the testis-specific PRDX4t is likely involved in spermatogenesis through the oxidative folding of protamine. The dysfunction of PRDX4 leads to oxidative damage and ER stress, and is related to various diseases including diabetes and cancer. In this review article we refer to the results of biological and medical research in order to unveil the functional consequences of this unique member of the PRDX family.