Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility

被引：84

作者：

Tanikawa, Chizu ^{[1
]}

Ueda, Koji ^{[2
]}

Suzuki, Akari ^{[3
]}

Iida, Aritoshi ^{[3
]}

Nakamura, Ryoichi ^{[4
]}

Atsuta, Naoki ^{[4
]}

Tohnai, Genki ^{[4
]}

Sobue, Gen ^{[4
]}

Saichi, Naomi ^{[2
]}

Momozawa, Yukihide ^{[3
]}

Kamatani, Yoichiro ^{[3
]}

Kubo, Michiaki ^{[3
]}

Yamamoto, Kazuhiko ^{[3
,5
]}

Nakamura, Yusuke ^{[6
,7
,8
]}

Matsuda, Koichi ^{[1
,9
]}

机构：

[1] Univ Tokyo, Inst Med Sci, Human Genome Ctr, Lab Mol Med, Tokyo 1088639, Japan

[2] Japanese Fdn Canc Res, Canc Precis Med Ctr, Project Personalized Canc Med, 3-8-31 Ariake, Tokyo 1358550, Japan

[3] RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa 2308560, Japan

[4] Nagoya Univ, Grad Sch Med, Dept Neurol, Nagoya, Aichi 4668560, Japan

[5] Univ Tokyo, Grad Sch Med, Dept Allergy & Rheumatol, Tokyo 1138654, Japan

[6] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA

[7] Univ Chicago, Dept Surg, 5841 S Maryland Ave, Chicago, IL 60637 USA

[8] Univ Chicago, Ctr Personalized Therapeut, Chicago, IL 60637 USA

[9] Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Lab Clin Genome Sequencing, Tokyo, Japan

来源：

CELL REPORTS | 2018年 / 22卷 / 06期

基金：

日本学术振兴会;

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; RHEUMATOID-ARTHRITIS; ARGININE METHYLATION; DEIMINASE; MUTATIONS; DISEASE; TDP-43; GENES; RESIDUES;

D O I：

10.1016/j.celrep.2018.01.031

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1473 / 1483

页数：11

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