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

Li Jiang1, Xiao-bing Chen1, Qian Wu1, Hai-ying Zhu1, Cheng-yong Du2, Mei-dan Ying1, Qiao-jun He1,3,4, Hong Zhu1, Bo Yang1, Ji Cao1,3,4
1 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2 Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310006, China
3 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310058, China
4 Cancer center of Zhejiang University, Hangzhou 310058, China
Correspondence to: Ji Cao:,
DOI: 10.1038/s41401-020-00531-1
Received: 8 March 2020
Accepted: 7 September 2020
Advance online: 6 October 2020


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.
Keywords: DJ-1; C terminus; homodimerization; methylglyoxal (MGO) detoxification; deglycation; ferroptosis; HEK293T cells; DJ-1−/− mouse embryonic fibroblast cells

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