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

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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 languageEnglish
Pages (from-to)1473-1483
Number of pages11
JournalCell Reports
Volume22
Issue number6
DOIs
Publication statusPublished - 06-02-2018

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Amyotrophic Lateral Sclerosis
Field effect transistors
Agglomeration
RNA-Binding Protein FUS
Proteins
Proteome
Methylation
Post Translational Protein Processing
RNA-Binding Protein EWS
Neurodegenerative diseases
Consensus Sequence
Arsenic
arginine deiminase
peptidylarginine deiminase type IV
Neurodegenerative Diseases
Proteomics
Solubility
Substrates
Fibroblasts
Odds Ratio

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Tanikawa, C., Ueda, K., Suzuki, A., Iida, A., Nakamura, R., Atsuta, N., ... Matsuda, K. (2018). Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility. Cell Reports, 22(6), 1473-1483. https://doi.org/10.1016/j.celrep.2018.01.031
Tanikawa, Chizu ; Ueda, Koji ; Suzuki, Akari ; Iida, Aritoshi ; Nakamura, Ryoichi ; Atsuta, Naoki ; Tohnai, Genki ; Sobue, Gen ; Saichi, Naomi ; Momozawa, Yukihide ; Kamatani, Yoichiro ; Kubo, Michiaki ; Yamamoto, Kazuhiko ; Nakamura, Yusuke ; Matsuda, Koichi. / Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility. In: Cell Reports. 2018 ; Vol. 22, No. 6. pp. 1473-1483.
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Tanikawa, C, Ueda, K, Suzuki, A, Iida, A, Nakamura, R, Atsuta, N, Tohnai, G, Sobue, G, Saichi, N, Momozawa, Y, Kamatani, Y, Kubo, M, Yamamoto, K, Nakamura, Y & Matsuda, K 2018, 'Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility', Cell Reports, vol. 22, no. 6, pp. 1473-1483. https://doi.org/10.1016/j.celrep.2018.01.031

Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility. / Tanikawa, Chizu; Ueda, Koji; Suzuki, Akari; Iida, Aritoshi; Nakamura, Ryoichi; Atsuta, Naoki; Tohnai, Genki; Sobue, Gen; Saichi, Naomi; Momozawa, Yukihide; Kamatani, Yoichiro; Kubo, Michiaki; Yamamoto, Kazuhiko; Nakamura, Yusuke; Matsuda, Koichi.

In: Cell Reports, Vol. 22, No. 6, 06.02.2018, p. 1473-1483.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility

AU - Tanikawa, Chizu

AU - Ueda, Koji

AU - Suzuki, Akari

AU - Iida, Aritoshi

AU - Nakamura, Ryoichi

AU - Atsuta, Naoki

AU - Tohnai, Genki

AU - Sobue, Gen

AU - Saichi, Naomi

AU - Momozawa, Yukihide

AU - Kamatani, Yoichiro

AU - Kubo, Michiaki

AU - Yamamoto, Kazuhiko

AU - Nakamura, Yusuke

AU - Matsuda, Koichi

PY - 2018/2/6

Y1 - 2018/2/6

N2 - 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.

AB - 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.

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