Abstract
Recent proteome analyses have provided a comprehensive overview of various posttranslational modifications (PTMs); however, PTMs involving protein citrullination remain unclear. We performed a proteomic analysis of citrullinated proteins, and we identified more than 100 PAD4 (peptidyl arginine deiminase 4) substrates. Approximately one-fifth of the PAD4 substrates contained an RG/RGG motif, and PAD4 competitively inhibited the methylation of the RGG motif in FET proteins (FUS, EWS, and TAF15) and hnRNPA1, which are causative genes for ALS (amyotrophic lateral sclerosis). PAD4-mediated citrullination significantly inhibited the aggregation of FET proteins, a frequently observed feature in neurodegenerative diseases. FUS protein levels in arsenic-induced stress granules were significantly increased in Padi4 −/− mouse embryonic fibroblasts (MEFs). Moreover, rs2240335 was associated with low expression of PADI4 in the brain and a high risk of ALS (p = 0.0381 and odds ratio of 1.072). Our findings suggest that PAD4-mediated RGG citrullination plays a key role in protein solubility and ALS pathogenesis. Tanikawa et al. report a role of PAD4 in protein aggregation and ALS. Proteome analysis revealed the RG/RGG motif as a consensus sequence for PAD4-mediated citrullination. PAD4 inhibits the methylation and aggregation of FET proteins. rs2240335 in PADI4 is associated with low PADI4 expression and a high risk of ALS.
Original language | English |
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Pages (from-to) | 1473-1483 |
Number of pages | 11 |
Journal | Cell Reports |
Volume | 22 |
Issue number | 6 |
DOIs | |
Publication status | Published - 06-02-2018 |
Externally published | Yes |
All Science Journal Classification (ASJC) codes
- General Biochemistry,Genetics and Molecular Biology