The C terminus of DJ-1 determines its homodimerization, MGO detoxification activity and suppression of ferroptosis

• Published in: Acta pharmacologica Sinica Vol. 42; no. 7; pp. 1150 - 1159
• Main Authors: Jiang, Li, Chen, Xiao-bing, Wu, Qian, Zhu, Hai-ying, Du, Cheng-yong, Ying, Mei-dan, He, Qiao-jun, Zhu, Hong, Yang, Bo, Cao, Ji
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.07.2021; Nature Publishing Group
• Subjects: Age; Amino Acid Sequence; Animals; Biomedical and Life Sciences; Biomedicine; C-Terminus; Detoxification; Embryo fibroblasts; Enzymatic activity; Ferroptosis; Ferroptosis - physiology; Gene deletion; HEK293 Cells; Humans; Hydrophobicity; Immunology; Internal Medicine; Medical Microbiology; Mice; Movement disorders; Mutation; Myc protein; Neurodegenerative diseases; PARK7 protein; Parkinson's disease; Pharmacology/Toxicology; Protein Deglycase DJ-1 - metabolism; Protein Multimerization - physiology; Pyruvaldehyde; Pyruvaldehyde - metabolism; Vaccine; methylglyoxal (MGO) detoxification; C terminus; HEK293T cells; homodimerization; deglycation; ferroptosis; mouse embryonic fibroblast cells; DJ-1; DJ-1−/− mouse embryonic fibroblast cells
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-020-00531-1

DJ-1 is a multifunctional protein associated with cancers and autosomal early-onset Parkinson disease. Besides the well-documented antioxidative stress activity, recent studies show that DJ-1 has deglycation enzymatic activity and anti-ferroptosis effect. It has been shown that DJ-1 forms the homodimerization, which dictates its antioxidative stress activity. In this study, we investigated the relationship between the dimeric structure of DJ-1 and its newly reported activities. In HEK293T cells with Flag-tagged and Myc-tagged DJ-1 overexpression, we performed deletion mutations and point mutations, narrowed down the most critical motif at the C terminus. We found that the deletion mutation of the last three amino acids at the C terminus of DJ-1 (DJ-1 ΔC3) disrupted its homodimerization with the hydrophobic L187 residue being of great importance for DJ-1 homodimerization. In addition, the ability in methylglyoxal (MGO) detoxification and deglycation was almost abolished in the mutation of DJ-1 ΔC3 and point mutant L187E compared with wild-type DJ-1 (DJ-1 WT). We also showed the suppression of erastin-triggered ferroptosis in DJ-1 −/− mouse embryonic fibroblast cells was abolished by ΔC3 and L187E, but partially diminished by V51C. Thus, our results demonstrate that the C terminus of DJ-1 is crucial for its homodimerization, deglycation activity, and suppression of ferroptosis.