Journal
ACTA PHARMACOLOGICA SINICA
Volume 42, Issue 7, Pages 1150-1159Publisher
NATURE PUBL GROUP
DOI: 10.1038/s41401-020-00531-1
Keywords
DJ-1; C terminus; homodimerization; methylglyoxal (MGO) detoxification; deglycation; ferroptosis; HEK293T cells; DJ-1(--)mouse embryonic fibroblast cells
Funding
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
- National Natural Science Foundation of China [81773757, 81402951]
- Zhejiang Medical and Health Science and Technology Program [2020384517]
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Experimental findings demonstrate that the C terminus of DJ-1 is crucial for its homodimerization, deglycation activity, and suppression of ferroptosis.
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 Delta C3) 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 Delta C3 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 Delta C3 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.
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