2. Academic Validation
  3. The C terminus of DJ-1 determines its homodimerization, MGO detoxification activity and suppression of ferroptosis

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

  • Acta Pharmacol Sin. 2021 Jul;42(7):1150-1159. doi: 10.1038/s41401-020-00531-1.
Li Jiang  # 1,  Xiao-Bing Chen  # 1,  Qian Wu 1,  Hai-Ying Zhu 1,  Cheng-Yong Du 2,  Mei-Dan Ying 1,  Qiao-Jun He 1 3 4,  Hong Zhu 1,  Bo Yang 1,  Ji Cao 5 6 7
Affiliations

Affiliations

  • 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.
  • 5 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. caoji88@zju.edu.cn.
  • 6 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310058, China. caoji88@zju.edu.cn.
  • 7 Cancer center of Zhejiang University, Hangzhou, 310058, China. caoji88@zju.edu.cn.
  • # Contributed equally.
PMID: 33024240 DOI: 10.1038/s41401-020-00531-1
Abstract

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

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

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