Characterization of the endoplasmic reticulum-resident peroxidases GPx7 and GPx8 shows the higher oxidative activity of GPx7 and its linkage to oxidative protein folding

Shingo Kanemura, Elza Firdiani Sofia, Naoya Hirai, Masaki Okumura, Hiroshi Kadokura, Kenji Inaba

Research output: Contribution to journalArticlepeer-review

Abstract

Oxidative protein folding occurs primarily in the mammalian endoplasmic reticulum, enabled by a diverse network comprising more than 20 members of the protein disulfide isomerase (PDI) family and more than five PDI oxidases. Although the canonical disulfide bond formation pathway involving Ero1α and PDI has been well-studied so far, the physiological roles of the newly identified PDI oxidases, glutathione peroxidase-7 (GPx7) and -8 (GPx8), are only poorly understood. We here demonstrated that human GPx7 has much higher reactivity with H2O2 and hence greater PDI oxidation activity than human GPx8. The high reactivity of GPx7 is due to the presence of a catalytic tetrad at the redox-active site, which stabilizes the sulfenylated species generated upon the reaction with H2O2 Although it was previously postulated that GPx7 catalysis involved a highly reactive peroxidatic cysteine that can be sulfenylated by H2O2, we revealed that a resolving cysteine instead regulates the PDI oxidation activity of GPx7. We also determined that GPx7 formed complexes preferentially with PDI and P5 in H2O2-treated cells. Altogether, these results suggest that human GPx7 functions as an H2O2-dependent PDI oxidase in cells, whereas PDI oxidation may not be the central physiological role of human GPx8.

Original languageEnglish
Pages (from-to)12772-12785
Number of pages14
JournalThe Journal of biological chemistry
Volume295
Issue number36
DOIs
Publication statusPublished - 2020 Sep 4

Keywords

  • disulfide
  • endoplasmic reticulum (ER)
  • glutathione peroxidase
  • hydrogen peroxide
  • oxidation–reduction (redox)
  • protein folding
  • protein-disulfide isomerase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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