Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility
Chizu Tanikawa,
Koji Ueda,
Akari Suzuki,
Aritoshi Iida,
Ryoichi Nakamura,
Naoki Atsuta,
Genki Tohnai,
Gen Sobue,
Naomi Saichi,
Yukihide Momozawa,
Yoichiro Kamatani,
Michiaki Kubo,
Kazuhiko Yamamoto,
Yusuke Nakamura,
Koichi Matsuda
Affiliations
Chizu Tanikawa
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Koji Ueda
Project for Personalized Cancer Medicine, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Tokyo 135-8550, Japan
Akari Suzuki
RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
Aritoshi Iida
RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
Ryoichi Nakamura
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
Naoki Atsuta
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
Genki Tohnai
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
Gen Sobue
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
Naomi Saichi
Project for Personalized Cancer Medicine, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Tokyo 135-8550, Japan
Yukihide Momozawa
RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
Yoichiro Kamatani
RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
Michiaki Kubo
RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
Kazuhiko Yamamoto
RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8654, Japan
Yusuke Nakamura
Departments of Medicine and Surgery and Center for Personalized Therapeutics, The University of Chicago, Chicago, IL 60637, USA
Koichi Matsuda
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo 108-8639, Japan; Corresponding author
Summary: 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.
