Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility - PubMed (original) (raw)
. 2018 Feb 6;22(6):1473-1483.
doi: 10.1016/j.celrep.2018.01.031.
Koji Ueda 2, Akari Suzuki 3, Aritoshi Iida 3, Ryoichi Nakamura 4, Naoki Atsuta 4, Genki Tohnai 4, Gen Sobue 4, Naomi Saichi 2, Yukihide Momozawa 3, Yoichiro Kamatani 3, Michiaki Kubo 3, Kazuhiko Yamamoto 5, Yusuke Nakamura 6, Koichi Matsuda 7
Affiliations
- PMID: 29425503
- DOI: 10.1016/j.celrep.2018.01.031
Free article
Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility
Chizu Tanikawa et al. Cell Rep. 2018.
Free article
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.
Keywords: ALS; EWS; FUS; PAD4; SNP; TAF15; citrulline; hnRNP; methylation; protein aggregation.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Miscellaneous