Oxidation of peroxiredoxin-4 induces oligomerization and promotes interaction with endoplasmic reticulum proteins

The family of peroxiredoxins catalyzes the reduction of hydrogen peroxide (H2O2). Peroxiredoxin 4 (PRDX4) is the only peroxiredoxin located within the endoplasmic reticulum (ER) and is the highest expressed ER H2O2 scavenger. PRDX4 has emerged as an important player in numerous diseases and its over-oxidation is a potential indicator of ER redox stress. The interactome of PRDX4 as well as the dynamics of its oligomerization have largely been unstudied. Therefore, the goal of this study was to determine the effect of oxidation on PRDX4 oligomerization and interaction with binding partners. We report that the oxidation of PRDX4 in lung epithelial cells treated with tertbutyl hydroperoxide (TBuOOH) caused a shift of PRDX4 from monomer/dimer to high molecular weight(HMW) species which are composed of PRDX4 containing sulfonic acid residues (PRDX4-SO3) as well as a complement of ER-associated proteins. Treatment of recombinant PRDX4 with TBuOOH also led to HMW complexes, showing that interactions with client proteins are not required for PRDX4 HMW complex formation.

过氧化物氧还蛋白（peroxiredoxins）家族可催化过氧化氢（H₂O₂）的还原反应。过氧化物氧还蛋白4（PRDX4）是唯一定位于内质网（ER）的过氧化物氧还蛋白，同时也是内质网中表达量最高的过氧化氢清除剂。PRDX4已被证实与多种疾病密切相关，其过度氧化可作为内质网氧化还原应激的潜在标志物。目前学界对PRDX4的相互作用组及其寡聚化动态过程的研究仍较为匮乏，因此本研究旨在探究氧化作用对PRDX4寡聚化进程及其与结合伴侣相互作用的影响。本研究发现，经叔丁基过氧化氢（TBuOOH）处理的肺上皮细胞中，PRDX4发生氧化后会从单体/二聚体形式转变为高分子量（HMW）复合物，该复合物由携带磺酸残基的PRDX4（PRDX4-SO3）以及一系列内质网相关蛋白共同组成。仅用TBuOOH处理重组PRDX4即可形成HMW复合物，这表明PRDX4组装高分子量复合物无需与其他结合蛋白发生相互作用。